@article {pmid41808074,
year = {2026},
author = {Lu, H and Chen, S and Tang, Y and He, W and Xia, S and Wu, Y},
title = {Sex differences in the associations between illness representations and behavioral intentions to seek early Alzheimer's detection in Chinese older adults.},
journal = {BMC geriatrics},
volume = {26},
number = {1},
pages = {},
pmid = {41808074},
issn = {1471-2318},
support = {Y202353191//General Scientific Research Project of the Zhejiang Provincial Department of Education/ ; 82271482//National Natural Science Foundation of China/ ; 2023ZY1018//Department of Science and Technology of Zhejiang Province/ ; OJQDSP2022013//Oujiang Laboratory/ ; },
abstract = {OBJECTIVES: Alzheimer’s disease (AD) is the most common form of dementia in older adults with no cure. Early detection and intervention are critical for improving patient outcomes. However, behavioral intentions to seek early detection of AD (BI-SEDAD) remain low. Illness representations, referring to individuals’ beliefs about illness, may influence BI-SEDAD. This study aimed to investigate the associations between illness representations and BI-SEDAD among Chinese older adults, and potential sex differences in these associations.

METHODS: A survey was conducted among 509 Chinese older adults. Participants completed the assessment of BI-SEDAD and illness representations of AD. Moderation analyses were conducted using SPSS PROCESS.

RESULTS: Consequences (β = 0.26), timeline (β = 0.23), illness identity (β = 0.22), illness coherence (β = 0.21), illness concern (β = 0.22), and emotional representations (β = 0.24) were positively associated with BI-SEDAD, whereas treatment control was negatively associated (β = − 0.10). Moreover, sex significantly moderated the associations between BI-SEDAD and consequences (β = − 0.20), treatment control (β = 0.21), illness identity (β = − 0.17), illness coherence (β = − 0.25), and illness concern (β = − 0.26). Specifically, the associations between BI-SEDAD and consequences, illness identity, illness coherence, and illness concern were stronger in males than in females. The association between BI-SEDAD and treatment control was significant only in males.

CONCLUSIONS: Illness representations are important predictors of BI-SEDAD, with notable sex differences. Tailored interventions that address key beliefs and consider sex differences may promote early detection in older populations.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12877-026-07288-y.},
}

@article {pmid41870777,
year = {2026},
author = {Mostafa, RE and Asaad, GF},
title = {Bridging the gaps in alzheimer's disease: a comprehensive review of current and emerging therapies.},
journal = {Inflammopharmacology},
volume = {34},
number = {4},
pages = {2219-2241},
pmid = {41870777},
issn = {1568-5608},
abstract = {Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide, accounting for 60–80% of dementia cases. It is characterized by gradual cognitive decline, neuronal loss, and pathological hallmarks, including amyloid-β (Aβ) plaques and neurofibrillary tangles of hyperphosphorylated tau protein. This review provides a comprehensive overview of AD, emphasizing its etiology, molecular mechanisms, risk factors, and current therapeutic strategies. Multiple hypotheses, including the amyloid cascade, tau, cholinergic, vascular, and neuroinflammatory theories, are discussed to elucidate disease pathogenesis. Genetic mutations in the APP, PSEN1, and PSEN2 genes, along with environmental and lifestyle factors, are shown to influence disease onset and progression. The treatment landscape is rapidly evolving from traditional symptomatic therapies, such as cholinesterase inhibitors and NMDA receptor antagonists, to emerging disease-modifying agents targeting amyloid, tau, and neuroinflammation. Novel approaches, including glutaminyl cyclase inhibitors, PDE inhibitors, serotonin receptor modulators, and metabolic therapies, offer new hope for altering disease progression. Non-pharmacological interventions, such as diet, exercise, and lifestyle modifications, also play a key preventive role. Despite ongoing challenges, advancements in biomarker research, neuroimaging, and precision medicine are improving early detection and individualized treatment strategies. Continuous innovation in pharmacotherapy and diagnostics promises to reshape the future of AD management and enhance patients’ quality of life. The current review focuses on bridging the gaps in AD’s current and emerging Therapies.},
}

@article {pmid41991715,
year = {2026},
author = {Wei, P and Zhu, T and Hashimoto, K and Jia, M and Yang, JJ},
title = {Exploring the lung-brain axis in perioperative neurocognitive disorders: a potential therapeutic target.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41991715},
issn = {1476-5578},
support = {82571352//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82571374//National Natural Science Foundation of China (National Science Foundation of China)/ ; 2024M761822//China Postdoctoral Science Foundation/ ; },
abstract = {Perioperative neurocognitive disorders (PND), primarily including postoperative delirium (POD) and postoperative cognitive dysfunction (POCD), are common and serious complications in elderly surgical patients. However, the exact mechanisms underlying PND are not fully understood. The lung-brain axis has recently been recognized as an important pathway in neurodegenerative diseases such as Alzheimer's disease (AD). Given that PND shares pathological features with AD, such as amyloid-β (Aβ) accumulation, the lung-brain axis may also represent a plausible mechanistic contributor to PND. Furthermore, elderly surgical patients often receive inhalation anesthetics and undergo mechanical ventilation during general anesthesia, which directly affect the lungs and may alter the pulmonary microenvironment. Therefore, we hypothesize that the lung-brain axis plays a role in the development of PND. In this article, we discuss potential mechanisms by which surgery and anesthesia-especially inhalation anesthetics and mechanical ventilation-may influence cognitive function via the lung-brain axis. Potential mechanisms include changes in the pulmonary microbiota, secretion of brain-derived neurotrophic factor, and lung-derived inflammatory responses. These pathways may disrupt the blood-brain barrier, promote neuroinflammation, and exacerbate Aβ deposition, ultimately leading to cognitive impairment. Exploring the role of the lung-brain axis could provide new insights into PND pathophysiology and reveal potential targets for prevention and treatment of PND by targeting pulmonary-mediated cascades.},
}

@article {pmid41991786,
year = {2026},
author = {Flores-Melivilu, D and Carrazana, E and García, N and Alarcón, S and Caru-Ruiz, M and Chacón-Fuentes, M and Santos, N and Ahumada, M and Nova, E and Diaz-Espinoza, R and Sanhueza, M and Hormazábal, E and Salvadores, N},
title = {Aristotelia chilensis Fruit Extracts Exhibit Neuroprotective Properties Against Alzheimer's Disease Related Mechanisms.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {41991786},
issn = {1559-1182},
mesh = {*Plant Extracts/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Fruit/chemistry ; *Neuroprotective Agents/pharmacology/therapeutic use ; Amyloid beta-Peptides/metabolism ; Animals ; Cell Survival/drug effects ; Humans ; Glutamic Acid/toxicity ; Acetylcholinesterase/metabolism ; Neurons/drug effects/metabolism/pathology ; *Elaeocarpaceae/chemistry ; },
abstract = {Aristotelia chilensis (maqui) extracts have garnered interest for their potential bioactivity, yet their specific effects on Alzheimer's disease (AD) pathology remain understudied. This study evaluated the neuroprotective properties of white and black maqui fruit extracts against glutamate-induced excitotoxicity and β-amyloid (Aβ) fibrillogenesis in vitro. Pre-treatment with maqui extracts significantly mitigated glutamate toxicity, increasing cell viability from 26.8% in glutamate-treated cells to 49.9% and 48.8% for white and black maqui, respectively. Furthermore, the extracts reduced Fluorojade C-positive degenerating neurons by up to 86.4% compared to the glutamate control. The extracts also exhibited potent anti-fibrillogenic activity, suppressing Aβ fibril formation by up to 77% in the ThT assay. Electron microscopy confirmed this inhibitory effect by showing a reduction in fibrillar structures. In contrast, neither extract inhibited acetylcholinesterase nor butyrylcholinesterase activity. Together, these results indicate that maqui fruits contain compounds capable of modulating key pathological features of AD in vitro, supporting their potential for further investigation.},
}

*Plant Extracts/pharmacology/therapeutic use
*Alzheimer Disease/drug therapy/pathology/metabolism
*Fruit/chemistry
*Neuroprotective Agents/pharmacology/therapeutic use
Amyloid beta-Peptides/metabolism
Animals
Cell Survival/drug effects
Humans
Glutamic Acid/toxicity
Acetylcholinesterase/metabolism
Neurons/drug effects/metabolism/pathology
*Elaeocarpaceae/chemistry

@article {pmid41992414,
year = {2026},
author = {Micocci, S and Parisotto, S and Alberti, D and Lanfranco, A and Bitonto, V and Renzi, P and Salmi, M and Bello, FD and Pagano, K and Ragona, L and Protti, N and Deagostino, A and Geninatti Crich, S},
title = {Carboranyl-Curcuminoids for the Neutron Capture-Based Treatment of Amyloid Aggregates in Alzheimer's Disease.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e21701},
doi = {10.1002/advs.202521701},
pmid = {41992414},
issn = {2198-3844},
support = {D13C22003520001//Dipartimenti di Eccellenza/ ; D13C25000220007)//Compagnia di San Paolo/ ; 964934//H2020 Future and Emerging Technologies/ ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. The aggregation of amyloid-beta (Aβ) peptides into oligomers and fibrils is central to its pathogenesis. While oligomers represent the most neurotoxic species, larger aggregates serve as reservoirs, maintaining pathological Aβ levels. To our knowledge, this study is the first to investigate Boron Neutron Capture Therapy (BNCT) as a method to selectively destabilize Aβ aggregates. This is achieved by inducing structural modifications in the Aβ peptide, aiming to convert fibrils into innocuous species. The approach utilizes [10]B-enriched monocarbonyl analogs of curcumin (BMACs), a novel molecule that binds to Aβ fibrils and enables the site-specific release of high-linear-energy-transfer (LET) α particles and lithium ions upon neutron exposure. In vitro, Aβ aggregates were characterized using FESEM and Thioflavin T staining. The binding affinities of BMACs were determined through competition assays, with inhibition constants calculated using the Cheng-Prusoff equation. Post-irradiation analysis by [1]H-NMR and mass spectrometry demonstrated selective oxidation of histidine residues, a chemical modification capable of inducing fibril destabilization. This study provides proof of concept that not only offers future perspectives for Alzheimer's treatment but also enhances the understanding of radiation effects on proteins, particularly within the context of amyloidosis.},
}

@article {pmid41992726,
year = {2026},
author = {Evers, A and Watson, K and Abbasi, F and Haque, K and Verma, A and Eitan, E and Rasgon, N},
title = {Insights from changes in NDEV biomarkers of metabolism: Effects of PPARγ and GLP1 receptor agonists on brain metabolism.},
journal = {The Journal of clinical endocrinology and metabolism},
volume = {},
number = {},
pages = {},
doi = {10.1210/clinem/dgag176},
pmid = {41992726},
issn = {1945-7197},
abstract = {BACKGROUND: Insulin resistance (IR) is implicated in central nervous system disorders, including depression and Alzheimer's disease (AD).

METHODS: We analyzed biological samples from two cohorts of clinical trial participants: 1) participants with unremitted depression after six months of treatment as usual who received pioglitazone (PPARγ agonist, N = 12) or placebo and 2) middle-aged participants at genetic risk for AD who received liraglutide (glucagon-like peptide 1 [GLP1] receptor agonist, N = 15) or placebo. These cohorts, which previously showed treatment-related improvements in peripheral IR, were used to assess the effects of pioglitazone and liraglutide on CNS insulin signaling using neuron-derived extracellular vesicles (NDEVs) as biomarkers. We utilized biological samples to measure biomarkers of IR in NDEVs. Eleven Akt-mTOR pathway proteins were measured before and after 12 weeks of treatment in both groups.

RESULTS: Participants who received pioglitazone experienced broader changes, with significant increases in GSK3β (Ser9), mTOR (Ser2448), and RPS6 (Ser235/Ser236; all p ≤ 0.02) compared to placebo, and 77% of participants showed mTOR (Ser2448) response. Participants who received liraglutide demonstrated significantly increased NDEV-associated phosphorylated Akt (Ser473) and mTOR (Ser2448; p = 0.04 and p = 0.025, respectively) compared to placebo, with 40% and 30% of participants in the liraglutide group showing biomarker response in both Akt (Ser473) and mTOR (Ser2448), respectively. These effects appeared relatively independent from changes in fasting plasma insulin and glucose concentration at 120-minutes during the oral glucose tolerance test.

DISCUSSION: Our findings demonstrate CNS-specific biomarker responses to both PPARγ agonists and GLP1 receptor agonists.},
}

@article {pmid41993246,
year = {2026},
author = {Pattanashetty, SG and Serrano, PA and Rockwell, P and Xie, L and Figueiredo-Pereira, ME},
title = {Terazosin drives sex-dependent adrenergic-bioenergetic reprogramming to restore network function in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.02.716175},
pmid = {41993246},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) has long been defined by amyloid-β plaques and hyperphosphorylated tau, yet disease-modifying therapies remain critically limited. Growing evidence reframes AD as a system-level failure driven by early dysregulation of synaptic, metabolic, and neuroimmune pathways, preceding overt protein aggregation and originating in selectively vulnerable circuits, including the locus coeruleus (LC)-hippocampal noradrenergic axis. This complexity underscores the need for therapeutic strategies that engage the disease at a network level, early in its trajectory. To this end, using a machine learning-based systems pharmacology framework for drug repurposing applied to human AD transcriptomic datasets, we identified terazosin (TZ) as a candidate predicted to reverse AD-associated molecular signatures. TZ is an FDA-approved α1-adrenergic receptor antagonist and phosphoglycerate kinase-1 activator. It was administered chronically via the diet (0.5 mg/kg bw/day) to male and female TgF344-AD rats and wild-type littermates from 5 to 11 months of age, preceding overt pathology. Bulk hippocampal RNA sequencing revealed sex-specific transcriptional remodeling in transgenic rats, strongly conserved with human AD datasets. Male TgF344-AD rats exhibited suppression of synaptic and transcriptional maintenance pathways with concurrent activation of metabolic, proteostatic, extracellular matrix, and vascular stress responses; females showed suppression of survival and vascular structural signaling alongside heightened DAM-like immune activation, amyloid-associated stress, and cell death programs. TZ reversed these signatures in a sex-dependent manner: males showed enhanced immune surveillance and reduced proteostasis burden, while females showed reinforcement of synaptic, survival, and metabolic pathways. TgF344-AD rats displayed selective LC-derived hippocampal noradrenergic axonopathy without global neuronal loss. TZ preserved fiber integrity preferentially in females and partially reversed LC vulnerability-associated transcriptional signatures in both sexes. TZ also reduced amyloid-β plaque burden in both sexes, attenuated hyperphosphorylated tau exclusively in females, and induced microglial morphological shifts in males. Finally, TZ restored wild-type spatial learning in transgenic animals, with females appearing to derive the greater cognitive benefit. Together, these findings demonstrate that TZ induced systems-level reprogramming of AD-relevant molecular pathways and preserved vulnerable noradrenergic circuitry in a sex-dependent manner. Moreover, TZ rescued spatial cognition in transgenic rats, with cognitive gains seemingly more pronounced in females. These results support adrenergic-bioenergetic modulation as a translational strategy for early-stage AD and underscore the necessity of sex as a biological variable in disease-modifying treatment development.},
}

@article {pmid41993389,
year = {2026},
author = {Negida, A and , },
title = {Alpha-synuclein co-pathology amplifies amyloid-driven tau accumulation across Braak stages without modifying tau-cognition associations.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.31.713304},
pmid = {41993389},
issn = {2692-8205},
abstract = {INTRODUCTION: Alpha-synuclein (αSyn) is the most common co-pathology in Alzheimer's disease (AD), yet its role within the amyloid-tau-neurodegeneration (ATN) cascade is unknown.

METHODS: We analyzed 636 ADNI participants with CSF αSyn seed amplification assay, amyloid PET, regional tau PET (Braak I-VI), structural MRI, and cognitive composites. Interaction models tested whether αSyn modifies the amyloid-tau and tau-cognition associations.

RESULTS: αSyn positivity (19.0%) amplified the amyloid-tau association across all Braak stages (meta-temporal interaction β = 0.258, 95% CI 0.104-0.411, p = 0.001), with strongest effects in Braak III-IV. αSyn did not modify tau-cognition associations in any domain (all interaction p > 0.18).

DISCUSSION: αSyn co-pathology selectively amplifies amyloid-driven tau propagation without modifying downstream tau-cognition relationships, identifying a node-specific effect within the ATN cascade with implications for patient stratification.

RESEARCH IN CONTEXT: Systematic review: We searched PubMed for studies combining α-synuclein seed amplification assays with amyloid and tau PET in Alzheimer's disease. One recent study (Franzmeier et al., 2025) demonstrated that α-synuclein co-pathology accelerates amyloid-driven tau accumulation. No study has examined whether α-synuclein modifies the downstream tau-cognition relationship or assessed regional tau specificity across all Braak stages.Interpretation: In 636 ADNI participants, α-synuclein co-pathology amplified the amyloid-tau association across all Braak stages but did not modify tau-cognition relationships. This dissociation identifies α-synuclein as a node-specific modifier of the ATN cascade, acting at the amyloid-to-tau transition.Future directions: Longitudinal studies with serial tau PET and α-synuclein SAA are needed to establish temporality. Clinical trials should evaluate whether α-synuclein stratification improves prediction of anti-amyloid treatment response.},
}

@article {pmid41993400,
year = {2026},
author = {Kammala, AK and Tatiparthy, M and Sreenivasmurthy, SGS and Garza, KH and Budhwani, S and Richardson, L and Menon, R and Krishnan, B},
title = {Exofection as a Therapeutic Modality: Restoring P-gp Activity via Trophoblast-Derived EV in Neuroinflammatory Disorders.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.02.716001},
pmid = {41993400},
issn = {2692-8205},
abstract = {BACKGROUND: P-glycoprotein (P-gp/ABCB1) is a key efflux transporter that maintains barrier integrity by clearing xenobiotics and toxic metabolites. At the feto-maternal interface, trophoblast-derived extracellular vesicles (CTC-EVs) naturally and transiently transfer functional P-gp to maternal decidual cells, restoring lost and or reduced P-gp function (exofection) to sustain pregnancy homeostasis. A similar loss of P-gp at the blood brain barrier (BBB) contributes to impaired amyloid-β (Aβ) clearance and neuroinflammation in Alzheimer's disease. We investigated whether CTC-EV-mediated exofection could restore P-gp function in human brain endothelial cells (hBECs) and enhance Aβ clearance under inflammatory and neurodegenerative conditions.

METHODS: CTC-EVs were isolated and characterized by nanoparticle tracking analysis and western blotting for P-gp and EV markers. Transcriptomic profiling of CTC-EVs identified enrichment of transporter-related genes, including solute carriers and ABC transporters, along with inflammatory mediators. Network analysis revealed coordinated modules linking EV cargo to transporter regulation, endocytosis/trafficking pathways, and inflammatory remodeling processes converging on BBB efflux activity. hBECs were exposed to LPS (500 ng/mL, 48 h) with or without CTC-EVs. P-gp expression was assessed by immunofluorescence (mean fluorescence intensity, MFI) and western blotting, while functional efflux was measured using Calcein-AM assays. Aβ oligomer transport was evaluated using a transwell hBEC model. In vivo, 3xTg-AD mice received intravenous CTC-EVs (1×10L/day for 5 days), followed by assessment of P-gp expression, Aβ burden, and neuroinflammatory markers. Pharmacokinetic studies in P-gp knockout mice were conducted to confirm functional transporter recovery.

RESULTS: LPS exposure significantly reduced P-gp expression in hBECs (41.3% decrease in MFI, p=0.0084), which was restored by CTC-EVs (46.7% increase vs. LPS, p=0.0121). Exofection increased P-gp by a 2.1-fold following EV treatment as determined by western blot. Functional assays demonstrated enhanced efflux, with a 38.5% reduction in intracellular Calcein fluorescence (p<0.001). Network-informed mechanisms supported coordinated regulation of transporter and trafficking pathways. CTC-EVs improved Aβ transport across inflamed hBEC monolayers. In vivo, EV-treated 3xTg-AD mice exhibited increased P-gp expression in the frontal cortex (38.6%) and hippocampus (42.1%), reduced Aβ plaque burden (27.9%), and decreased inflammatory markers (IL-1β and TNF-α, p<0.05). In P-gp knockout mice, EVs reduced brain drug accumulation by 22.4% (p=0.032), confirming restoration of transporter function.

CONCLUSION: CTC derived EVs are natural carriers of functional transporter proteins and restore efflux capacity in compromised endothelial barriers. Integration of transcriptomic and network analyses highlights coordinated regulation of transporter, trafficking, and inflammatory pathways underlying exofection. This reproductive biology inspired strategy offers a promising therapeutic approach for enhancing Aβ clearance and mitigating neuroinflammation in Alzheimer's disease.},
}

@article {pmid41993974,
year = {2026},
author = {Han, H and Hou, L and Lu, J and Sun, H and Ning, W and Liang, Y and Gu, Y and Yin, H and Gao, Q},
title = {The intellectual landscape of cognitive impairment in type 2 diabetes: knowledge structure, research focuses and rising trends.},
journal = {Frontiers in endocrinology},
volume = {17},
number = {},
pages = {1809245},
pmid = {41993974},
issn = {1664-2392},
mesh = {*Diabetes Mellitus, Type 2/complications/psychology ; Humans ; *Cognitive Dysfunction/etiology/epidemiology/psychology ; Bibliometrics ; *Biomedical Research/trends ; },
abstract = {BACKGROUND: Type 2 diabetes mellitus (T2DM) is prevalent worldwide, with cognitive dysfunction emerging as a significant complication. Despite extensive research into its pathological mechanisms and clinical management, the knowledge structure, research priorities, and developmental trends within this field remain unsystematically integrated.

METHODS: To ensure comprehensive coverage and compatibility with bibliometric analysis tools, relevant publications on type 2 diabetes mellitus (T2DM) and cognitive dysfunction were primarily retrieved from the Web of Science Core Collection (WOSCC) database from its inception to November 5, 2025. Searches were also conducted in PubMed and Scopus to verify completeness, but the final dataset was derived mainly from WOSCC due to its optimal export format for CiteSpace (plain text with full records and cited references) and high overlap after deduplication. Employing bibliometric methods and tools such as CiteSpace (version 6.4 Advanced) and SCImago Graphica (version 1.0.39), we conducted visual analyses of publication trends, country/region collaboration, institutional distribution, author contributions, journal impact, co-cited references, and keywords.

RESULTS: A total of 1,752 publications were included. Annual publication volume exhibited a marked upward trend, accelerating particularly after 2018. China, the United States, and the United Kingdom were the primary contributing nations, with close inter-institutional collaboration. High-frequency keywords included 'type 2 diabetes mellitus', 'Alzheimer's disease', and 'cognitive impairment'. Research focus has shifted from early risk factors to microscopic levels, including neuroimaging, gut microbiota, and molecular mechanisms.

CONCLUSION: Research on cognitive dysfunction in T2DM exhibits multidisciplinary characteristics, balancing fundamental research with clinical translation. Future efforts should enhance multidimensional integration of mechanism studies to advance early screening and personalised treatment strategies.},
}

*Diabetes Mellitus, Type 2/complications/psychology
Humans
*Cognitive Dysfunction/etiology/epidemiology/psychology
Bibliometrics
*Biomedical Research/trends

@article {pmid41994122,
year = {2026},
author = {Iglesias, JE and Johnson, IP and Williams-Ramirez, J and Zemlyanker, D and Tian, L and Gopinath, K and Olchanyi, M and Farnan, AD and Demopoulos, A and Rosen, MS and Sheth, KN and de Havenon, A and Kimberly, WT and Sorby-Adams, A},
title = {On the accuracy of image registration in portable low-field 3D brain MRI.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8255109/v1},
pmid = {41994122},
issn = {2693-5015},
abstract = {Portable low-field MRI offers an affordable and mobile alternative to conventional high-field scanners, enabling imaging in point-of-care and resource-limited settings. However, its lower signal-to-noise ratio, reduced resolution, and acquisition artifacts raise concerns about the accuracy of standard image registration methods. Reliable registration is critical for a wide range of emerging applications, including frequent brain monitoring, assessment of neurodegenerative disease progression, and evaluation of treatment effects such as those of Alzheimer's therapeutics. In this work, we systematically evaluated state-of-the-art registration approaches on simulated low-field scans (obtained by downsampling high-field images) and on real low-field brain MRI data. We compared three representative approaches: classical optimization (NiftyReg), learning-based registration (SynthMorph), and synthesis-based registration (SynthSR+NiftyReg). Using downsampled high-field scans, all methods performed well, achieving high Dice scores and smooth deformation fields, indicating that reduced resolution alone does not hinder registration. In contrast, real low-field data exhibited lower accuracy, primarily due to geometric distortion and other acquisition-specific artifacts. Among the tested approaches, the synthesis-based pipeline achieved the most robust performance across subjects and modalities. Overall, existing algorithms can accommodate resolution limitations, however, future methods could further enhance coregistration by explicitly addressing the distortions present in low-field MRI scans.},
}

@article {pmid41994275,
year = {2026},
author = {Yu, T and Yu, Y and Zhao, J and Li, H and Lu, H and Li, Y and Peng, Y and Wang, S and Wei, W and Cheng, X},
title = {Qifuyin improves physiological frailty by regulating the intestinal flora in 3xTg-AD mice.},
journal = {Frontiers in microbiology},
volume = {17},
number = {},
pages = {1753643},
pmid = {41994275},
issn = {1664-302X},
abstract = {OBJECTIVE: Alzheimer's disease (AD) is often accompanied by motor dysfunction, impaired limb strength, and gut microbiota disturbances. This study aimed to evaluate the effects of Qifuyin (QFY), a traditional Chinese medicine formula, on motor deficits, limb strength, aging, and gut microbiota composition in 3xTg-AD mice, a widely used model of AD.

METHODS: Male and female 3xTg-AD mice were administered QFY at low, medium, or high doses. Motor function was assessed using grip strength and rotarod tests. Aging was evaluated through aging scores. Gut microbiota composition was analyzed at the phylum, family, genus, and species levels. Functional profiling of microbiota was performed using KEGG, eggNOG, and carbohydrate-active enzyme (CAZyme) databases. Pearson correlation analyses were conducted to explore relationships between microbiota composition and motor performance.

RESULTS: QFY treatment significantly improved both absolute and normalized grip strength in male and female 3xTg-AD mice. Similarly, motor coordination, as assessed by latency to fall on the rotarod, was significantly enhanced in the groups of QFY. Aging scores were significantly reduced after the treatment of QFY. Microbiome analysis revealed that QFY treatment restored species diversity and improved the overall composition of gut microbiota, with significant increases in Muribaculaceae and decreases in Alcaligenaceae, Rhodanobacteraceae, and Spirochaetaceae. Principal component analysis (PCA) indicated that the gut microbiota composition of the QFY group resembled that of the control (Con) group. Functional analyses showed that treatment of QFY restored microbial pathways related to metabolism and genetic information processing, with significant correlations between microbial alterations and improved motor outcomes. Additionally, QFY modulated the abundance of key carbohydrate-active enzymes, including GH43 and GH35, which were positively correlated with grip strength and rotarod performance.

CONCLUSION: Qifuyin improves motor function, reduces aging-related deficits, and restores gut microbiota homeostasis in 3xTg-AD mice. These findings suggest that QFY may offer therapeutic potential for addressing frailty and motor dysfunction in AD, in association with alterations in gut microbiota composition and predicted microbial functions.},
}

@article {pmid41994888,
year = {2026},
author = {Yang, Z and Sang, P and Han, Y and Jiang, B and Kong, L and Zhou, X},
title = {Personalized treatment design in the context of functional confounding.},
journal = {Biometrics},
volume = {82},
number = {2},
pages = {},
doi = {10.1093/biomtc/ujag056},
pmid = {41994888},
issn = {1541-0420},
support = {12171242//National Natural Science Foundation of China/ ; 72342019//National Natural Science Foundation of China/ ; },
mesh = {Humans ; Alzheimer Disease/therapy/diagnostic imaging ; *Precision Medicine/methods/statistics & numerical data ; Computer Simulation ; Neuroimaging ; Machine Learning ; Disease Progression ; Confounding Factors, Epidemiologic ; Biometry/methods ; },
abstract = {One of the primary goals of individualized treatment rule (ITR) methodology is to identify optimal decision rules using clinical predictors. While functional data has become increasingly available in biomedical research, there has been limited work on incorporating functional data into ITR estimation, particularly in observational studies. In this paper, we propose a novel approach that integrates outcome-weighted learning (OWL) with reproducing kernel Hilbert space to determine optimal treatment regimes involving functional data. Furthermore, to address the issue of data piling, we employ the distance-weighted discrimination classifier instead of traditional support vector machines. We establish the theoretical consistency of the decision functional estimator with its risk bound. Extensive simulations and the analysis of the Alzheimer's Disease Neuroimaging Initiative dataset demonstrate the superior performance of our method compared to existing OWL approaches. The results highlight critical factors in Alzheimer's Disease progression and reveal limitations of the original OWL method in this context.},
}

Humans
Alzheimer Disease/therapy/diagnostic imaging
*Precision Medicine/methods/statistics & numerical data
Computer Simulation
Neuroimaging
Machine Learning
Disease Progression
Confounding Factors, Epidemiologic
Biometry/methods

@article {pmid41996008,
year = {2026},
author = {Woźniak-Mitał, J and Rasmus, P and Strombek-Milczarek, M and Kaźmierski, J},
title = {The Impact of Transcranial Direct Stimulation Therapy Combined with Intranasal Near-Infrared Stimulation on Cognitive Performance in Patients with Mild Cognitive Impairment and Alzheimer's Disease: A Pilot Randomized, Double-Blind, Placebo-Controlled Study.},
journal = {Neurology and therapy},
volume = {},
number = {},
pages = {},
pmid = {41996008},
issn = {2193-8253},
abstract = {INTRODUCTION: Alzheimer's disease (AD) and mild cognitive impairment (MCI) are progressive neurodegenerative conditions with limited therapeutic options. Neuromodulation techniques such as transcranial direct current stimulation (tDCS) and photobiomodulation (PBM) have shown promise in improving cognitive function, but their combined effects remain underexplored.

METHODS: In a pilot randomized, double-blind, placebo-controlled trial, 33 participants were assigned to either active or sham stimulation groups. The intervention consisted of 50 sessions over 10 weeks, with tDCS (2 mA, F3-F4 montage) and intranasal near-infrared stimulation (iNIRS) (850 nm, 40 Hz, 50% duty cycle) administered simultaneously. Cognitive outcomes were assessed using the Mini-Mental State Examination (MMSE) and ADAS-Cog at baseline, post-treatment, and at the 12-week follow-up.

RESULTS: Significant improvements were observed in the active group across both scales. MMSE scores increased from 21.89 ± 2.35 to 27.22 ± 1.96 (p = 0.0001), with sustained effects at follow-up. ADAS-Cog scores decreased from 34.78 ± 4.99 to 18.22 ± 4.4 (p < 0.0001). Post hoc analyses revealed significant changes in attention, recall, praxis, and executive domains. No serious adverse events were reported.

CONCLUSION: Combined tDCS and iNIRS therapy significantly enhances cognitive performance in patients with MCI and mild AD. This synergistic, non-invasive approach may offer a promising therapeutic strategy to delay cognitive decline and reduce care-related burdens.

TRIAL REGISTRATION: ClinicalTrials.gov NCT07290686; Registration date 14 December 2023.},
}

@article {pmid41997210,
year = {2026},
author = {Chakravarty, S and Revi, N and Bijukumar, D},
title = {Development and initial characterization of Ang-2 decorated exosome-liposome hybrid nanocarriers for BBB targeting capability: An evaluation of LRP-1 receptor mediated endocytosis.},
journal = {Biomedical materials (Bristol, England)},
volume = {},
number = {},
pages = {},
doi = {10.1088/1748-605X/ae6164},
pmid = {41997210},
issn = {1748-605X},
abstract = {Central Nervous System (CNS) diseases, including Parkinson's, Alzheimer's, and brain tumors, are among the most challenging conditions to treat and are associated with high mortality rates. A significant obstacle in conventional treatment methods for CNS diseases is that many drugs struggle to penetrate the blood-brain barrier (BBB), which diminishes their effectiveness. The primary aim of the current study was to develop and characterize a hybrid nanocarrier composed of exosomes and liposomes to facilitate targeted drug delivery across the BBB for future CNS disease therapies. To achieve targeted uptake, we conjugated the exosome-liposome hybrid to the Angiopep-2 peptide (ANG-2), which has a specific affinity for the LRP-1 receptor, found on endothelial cells of the blood-brain barrier. Our results indicate that exosome-liposome hybrid nanoparticles exhibit significantly greater stability than exosomes alone. Moreover, the LRP-1 ligand-decorated exo-lipo hybrids effectively targeted U87 cells (a model cell line that expresses LRP-1) more efficiently than HEK293 (a cell line with low LRP-1 expression). Additionally, our findings demonstrated that these nanocarriers successfully evaded lysosomal degradation in U87 cells. We also assessed the barrier-crossing efficiency of the nanocarriers in vivo using zebrafish embryos.},
}

@article {pmid41997281,
year = {2026},
author = {Yang, YP and Nicol, CJB and Yen, C and Chiang, MC},
title = {Glutathione-conjugated gold nanoparticles mitigate amyloid-beta-induced neuroinflammation and tauopathy through inhibition of NF-κB, the NLRP3 inflammasome axis in 3D human neural stem cell models.},
journal = {Experimental cell research},
volume = {},
number = {},
pages = {115030},
doi = {10.1016/j.yexcr.2026.115030},
pmid = {41997281},
issn = {1090-2422},
abstract = {Neuroinflammation and tauopathy are central pathological features of Alzheimer's disease (AD), often exacerbated by amyloid-β (Aβ) accumulation. This study evaluated the therapeutic potential of glutathione-conjugated gold nanoparticles (GSH-AuNPs) in mitigating Aβ-induced cytotoxicity and inflammation using a physiologically relevant 3D human neural stem cell (hNSCs) model cultured within a gelatin scaffold. This 3D system provided a tissue-like microenvironment to closely mimic in vivo conditions. GSH-AuNP treatment significantly rescued Aβ-induced loss of cell viability and suppressed tumor necrosis factor-α (TNF-α) secretion. At the molecular level, GSH-AuNPs downregulated the expression of key inflammatory mediators, including IKKα, IKKβ, and NF-κB (p65), and inhibited nuclear translocation of p65. Additionally, GSH-AuNPs attenuated the expression of proinflammatory enzymes iNOS and COX-2 and suppressed activation of the NLRP3 inflammasome, as evidenced by reduced levels of NLRP3, ASC, caspase-1, IL-1β, and IL-18. Proteostasis was improved by restoring chymotrypsin-like proteasome activity and reducing phosphorylated tau accumulation. Furthermore, GSH-AuNPs enhanced cellular resilience by upregulating heat shock factor 1 (HSF1) and normalizing the expression of key molecular chaperones HSP27, HSP70, and HSP90. Our findings highlight the multifaceted protective effects of GSH-AuNPs in counteracting Aβ-induced neuroinflammation and tauopathy. These results support the potential application of GSH-AuNPs as a nanomedicine-based therapeutic strategy for AD.},
}

@article {pmid41997401,
year = {2026},
author = {Sun, X and Deng, W and Yu, J and Xu, X},
title = {From mechanisms to therapeutics: The expanding role of cell-based strategies in Alzheimer's disease.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178867},
doi = {10.1016/j.ejphar.2026.178867},
pmid = {41997401},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline. Its core pathologies include the deposition of amyloid-β plaques, the formation of neurofibrillary tangles composed of hyperphosphorylated tau protein, chronic neuroinflammation, and neuronal loss. With the rapidly aging global population, the prevalence of AD continues to rise. Current pharmacological treatments offer only limited symptomatic relief and cannot modify the underlying disease trajectory, leaving a significant unmet clinical need. In this context, cell-based therapy has emerged as a promising therapeutic strategy, leveraging its unique multi-targeted and regenerative capacities. This review systematically examines the therapeutic potential of various cell types, including mesenchymal stem cells, neural stem cells, immune cells, and engineered cells. We elaborate on their mechanisms of action, which encompass neurotrophic support, immunomodulation, and clearance of pathological proteins. These concerted actions contribute to remodeling the hostile brain microenvironment and promoting neuroregeneration in AD. Although preclinical evidence is robust, the clinical translation of cellular therapies faces considerable challenges. These hurdles include selecting the optimal cell source, developing efficient delivery strategies, determining the ideal intervention timing, and establishing standardized manufacturing protocols. Looking forward, we discuss how the development of precise disease models, the integration of gene editing and engineering strategies, advances in combination therapies, and the establishment of personalized treatment regimens are poised to position cell therapy at the forefront of comprehensive AD management. These innovations hold new promise for achieving true disease modification.},
}

@article {pmid41997458,
year = {2026},
author = {Chen, F and Lv, X and Xiang, K and Lin, X and Dai, C and Wei, C and Zhang, Y and Liu, J and Li, J},
title = {Pterostilbene targets microglia-mediated neuroinflammation for Alzheimer therapy.},
journal = {The Journal of nutritional biochemistry},
volume = {},
number = {},
pages = {110382},
doi = {10.1016/j.jnutbio.2026.110382},
pmid = {41997458},
issn = {1873-4847},
abstract = {Microglia-mediated neuroinflammation is a key driver of Alzheimer's disease (AD) progression, exacerbating neuronal damage and pathological changes. Pterostilbene (PTE), a natural anti-inflammatory stilbenoid, shows neuroprotective potential in AD, but its specific mechanism in regulating AD-related neuroinflammation remains unclear. Here, we explored the anti-neuroinflammatory effect and mechanisms of PTE against AD. APPswe/PS1dE9 (APP/PS1) transgenic mice were treated intragastrically with PTE for 4 weeks, followed by evaluation of cognitive function and pathological changes. Amyloid-β (Aβ) burden, Tau protein phosphorylation, microglial activation and proinflammatory cytokines production were analyzed. To further investigate the potential mechanism of PTE, an integrated approach combining network pharmacology, RNA sequencing, molecular docking, molecular dynamics simulations, and cell transfection techniques were conducted. Our results showed that PTE treatment improved cognitive impairment, Aβ deposits, Tau protein phosphorylation, microglia activation, and production of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 in vivo and in vitro. Notably, molecular docking predicted that PTE has binding affinity for JAK2 at LYS-857, LYS-882, and LEU-932. Consistently, site-directed mutagenesis reduced the inhibitory effect of PTE on JAK2/STAT3 phosphorylation, supporting JAK2 as a functional target. Meanwhile, we revealed that PTE effectively inhibited activation of microglia in the APP/PS1 mice by regulating JAK2-STAT3 pathway. These findings indicate that PTE treatment could attenuate microglia-mediated neuroinflammation via regulating JAK2-STAT3 signaling pathway, which might provide a novel option to elucidate the effects of PTE on AD.},
}

@article {pmid41997498,
year = {2026},
author = {Pillarisetti, S and Alfieri, R and Palumbo, P and Sarmento, B and Celia, C and Fresta, M},
title = {Oxidative cues as theranostic switches for the ROS-responsive Nanotheranostics in oxidative stress-driven diseases.},
journal = {Journal of controlled release : official journal of the Controlled Release Society},
volume = {},
number = {},
pages = {114933},
doi = {10.1016/j.jconrel.2026.114933},
pmid = {41997498},
issn = {1873-4995},
abstract = {Nanotheranostics (NTs) are nanoscale systems that combine disease diagnosis and targeted therapy. They often respond to specific signals, such as reactive oxygen species (ROS). These platforms leverage elevated ROS levels associated with diseases, such as neurodegeneration, cancer, cardiovascular disorders, and inflammation, to control drug release and support targeted imaging. In this review, we have described the different roles of ROS in neurological disorders (Alzheimer's disease), cancer, cardiovascular diseases (including atherosclerosis and myocardial infarction), and joint inflammation (arthritis). We also discuss the relative applications of ROS-responsive NTs. By integrating diagnosis and treatment, ROS-responsive NTs can improve treatment outcomes, reduce side effects, and help clinicians track disease progression and therapeutic response in real time. Advanced NTs are sensitive to additional triggers, such as pH, thermal, and hypoxic conditions. This sensitivity improves accuracy and outcomes for ROS-driven diseases. This strategy shows promise for precision medicine by using multifunctional, stimulus-activated nanomedicines to treat diseases driven by oxidative stress. This review summarizes recent advances, focusing on nanomaterial composition and chemistry for ROS response or scavenging to improve diagnosis and treatment. Finally, we explore current advances and perspectives on ROS-based NTs across ROS-driven diseases.},
}

@article {pmid41985900,
year = {2026},
author = {Nonino, F and Minozzi, S and Sambati, L and Del Giovane, C and Baldin, E and Bassi, MC and De Santis, C and Gonzalez-Lorenzo, M and Vignatelli, L and Filippini, G and Richard, E},
title = {Amyloid-beta-targeting monoclonal antibodies for people with mild cognitive impairment or mild dementia due to Alzheimer's disease.},
journal = {The Cochrane database of systematic reviews},
volume = {4},
number = {4},
pages = {CD016297},
pmid = {41985900},
issn = {1469-493X},
mesh = {Humans ; *Alzheimer Disease/complications/drug therapy ; *Cognitive Dysfunction/drug therapy/etiology ; *Amyloid beta-Peptides/antagonists & inhibitors/immunology ; Randomized Controlled Trials as Topic ; *Antibodies, Monoclonal/therapeutic use/adverse effects ; Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects ; Aged ; },
abstract = {RATIONALE: Alzheimer's disease is a neurodegenerative disorder and the most common cause of dementia. Aggregated amyloid-beta protein deposits are implicated in its pathogenesis. Amyloid-beta-targeting monoclonal antibodies (sometimes represented as Aβ-mAbs) are potentially disease-modifying for Alzheimer's disease: through the clearance of amyloid in the brain, they may slow cognitive and functional decline.

OBJECTIVES: To assess the clinical benefits and harms of amyloid-beta-targeting monoclonal antibodies aducanumab, bapineuzumab, crenezumab, donanemab, gantenerumab, lecanemab, ponezumab, remternetug, and solanezumab in people with mild cognitive impairment or mild dementia due to Alzheimer's disease.

SEARCH METHODS: We searched CENTRAL, MEDLINE (PubMed), Embase, and two clinical trials registries (Clinicaltrials.gov and WHO International Clinical Trials Registry Platform), and we undertook reference checking and citation research. The most recent search date was 7 August 2025.

ELIGIBILITY CRITERIA: We included randomised controlled trials (RCTs) that lasted at least 12 months and compared amyloid-beta-targeting monoclonal antibodies with placebo or no treatment in people with mild cognitive impairment or mild dementia due to Alzheimer's disease. We included both parallel-group and cluster designs.

OUTCOMES: Our outcomes of critical importance were: cognitive function; dementia severity; functional ability; any amyloid-related imaging abnormality (ARIA), which includes oedema (E) and haemorrhage (H); any symptomatic ARIA E and H; symptomatic brain haemorrhage; serious adverse events; and any-cause mortality. We analysed data at 12, 18, 24, and over 24 months of treatment.

RISK OF BIAS: We used the Cochrane risk of bias tool RoB 2 to assess the risk of bias in outcomes of critical importance.

SYNTHESIS METHODS: We meta-analysed results for each outcome within each comparison using the inverse variance method and the random-effects model. We used GRADE to assess the certainty of evidence for each outcome as very low, low, moderate, or high.

INCLUDED STUDIES: Overall, we included 17 studies with 20,342 participants. The mean age of participants in the studies ranged from 70 to 74 years. Seven studies enroled only participants with mild dementia, and one study enroled only participants with mild cognitive impairment. The remaining studies included a mixed population. The mean duration of participants' cognitive impairment ranged from 17 to 52 months. The 17 studies assessed seven different amyloid-beta-targeting monoclonal antibodies: aducanumab (n = 3), bapineuzumab (n = 4), crenezumab (n = 2), donanemab (n = 1), gantenerumab (n = 4), lecanemab (n = 1), and solanezumab (n = 2). All used placebo as a comparison. Eleven studies lasted 18 months, four lasted 24 months, and two lasted more than 24 months. All studies were funded by the pharmaceutical industry.

SYNTHESIS OF RESULTS: Below, we report the results of the studies at 18 months. Cognitive function Compared to placebo, amyloid-beta-targeting monoclonal antibodies probably result in little to no difference in cognitive function as measured by the ADAS-Cog (Alzheimer's Disease Assessment Scale-Cognitive) scale (standardised mean difference (SMD) -0.11, 95% confidence interval (CI) -0.16 to -0.06; 13 studies, 9895 participants; moderate certainty). Dementia severity Amyloid-beta-targeting monoclonal antibodies may result in little to no difference in dementia severity as measured by the CDR-SB (Clincal Dementia Rating Sum of Boxes) scale (SMD -0.12, 95% CI -0.24 to -0.00; 9 studies, 8053 participants; low certainty). Functional ability Amyloid-beta-targeting monoclonal antibodies probably result in little to no difference in functional ability as measured on the ADCS-ADL (Alzheimer's Disease Cooperative Study - Activities of Daily Living) scale (SMD 0.09, 95% CI 0.03 to 0.16; 3 studies, 3478 participants; moderate certainty) and may result in a small increase in functional ability if measured with the ADCS-iADL (Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living) scale (SMD 0.21, 95% CI 0.10 to 0.32; 1 study, 1252 participants; low certainty) or ADCS-ADL-MCI (Alzheimer's Disease Cooperative Study - Activities of Daily Living for Mild Cognitive Impairment) scale (SMD 0.23, 95% CI 0.12 to 0.33; 4 studies, 2802 participants; low certainty). Adverse events Amyloid-beta-targeting monoclonal antibodies probably result in a small increase in the occurrence of any ARIA E (ARD (absolute risk difference) 107 more per 1000, 95% CI 77 more to 148 more; 11 studies, 13,595 participants; moderate certainty) and probably little to no difference in symptomatic ARIA E (ARD 29 more per 1000, 95% CI 22 more to 38 more; 2 studies, 3522 participants; moderate certainty) or symptomatic ARIA H (ARD 4 more per 1000, 95% CI 1 fewer to 31 more; 1 study, 1795 participants; moderate certainty). Three studies assessing any ARIA H showed heterogeneous results (I[2] = 81%), which prevented pooled analysis. At 18 months, amyloid-beta-targeting monoclonal antibodies do not increase serious adverse events (ARD 6 more events per 1000, 95% CI 10 fewer to 26 more; 9 studies, 11,904 participants; high certainty) or overall mortality (ARD 2 more events per 1000, 95% CI 3 fewer to 11 more; 7 studies, 9733 participants; high certainty). We judged the overall risk of bias as low for the outcomes of serious adverse events and mortality. We had some concerns about the overall risk of bias for efficacy outcomes, mainly due to the risk of functional unblinding (i.e. participants and investigators correctly guessing whether a participant is receiving the active drug or placebo because of noticeable side effects).

AUTHORS' CONCLUSIONS: The effect of amyloid-beta-targeting monoclonal antibodies on cognitive function and dementia severity at 18 months in people with mild cognitive impairment or mild dementia due to Alzheimer's disease is trivial, while on functional ability, it is small at best. Amyloid-beta-targeting monoclonal antibodies increase the risk of amyloid-related imaging abnormalities. Both desirable outcomes and adverse events were inconsistently reported in the studies included in the review. Successful removal of amyloid from the brain does not seem to be associated with clinically meaningful effects in people with mild cognitive impairment or mild dementia due to Alzheimer's disease. Future research on disease-modifying treatments for Alzheimer's disease should focus on other mechanisms of action.

FUNDING: This Cochrane review was funded in part by the Drug and Medical Devices Governance Area, Regione Emilia-Romagna, Bologna, Italy. The publication of this article was supported by "Ricerca Corrente" funding from the Italian Ministry of Health.

REGISTRATION: Protocol (2025): PROSPERO registration number CRD420251114325.},
}

Humans
*Alzheimer Disease/complications/drug therapy
*Cognitive Dysfunction/drug therapy/etiology
*Amyloid beta-Peptides/antagonists & inhibitors/immunology
Randomized Controlled Trials as Topic
*Antibodies, Monoclonal/therapeutic use/adverse effects
Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects
Aged

@article {pmid41986146,
year = {2026},
author = {Ebani, EJ and Yadav, D and Knight-Greenfield, A and Gardella, J and Moirano, J and Intorcia, B and RoyChoudhury, A and Keil, SA and Nordvig, AS and Blum, S and Lin, M and Osborne, JR and Chiang, GC and Ivanidze, J},
title = {Cross-Platform Concordance of Quantitative Amyloid PET Z-Scores in a Real-World Clinical Cohort of Patients with Cognitive Impairment and Suspected Alzheimer Disease.},
journal = {AJNR. American journal of neuroradiology},
volume = {},
number = {},
pages = {},
doi = {10.3174/ajnr.A9354},
pmid = {41986146},
issn = {1936-959X},
abstract = {BACKGROUND AND PURPOSE: Normative modeling tools are FDA-approved clinical software applications that enable quantitative amyloid PET analysis in routine clinical practice, however implementation differences may yield non-interchangeable Z-scores, with implications for diagnosis and treatment eligibility for patients with cognitive impairment and/or suspected Alzheimer disease. This study evaluated the agreement of Z-scores derived from two widely used clinical software packages in a real-world cohort of patients with cognitive impairment/Alzheimer disease.

MATERIALS AND METHODS: Amyloid PET from 100 consecutive patients with cognitive impairment/Alzheimer disease obtained as part of standard-of-care evaluation at a single institution were retrospectively reviewed. Amyloid PET were post-processed using syngo.via MI Neurology (Siemens Healthineers) and MIMneuro (MIM Software/GE Healthcare). Regional Z-scores were obtained for the temporal, precuneus, posterior cingulate, parietal, frontal, and anterior cingulate cortices. Z-scores were compared per patient and stratified by Centiloid burden (low/intermediate/high: < 20/20-30/>30). Agreement was evaluated using Bland-Altman analysis and Deming regression.

RESULTS: Agreement between Syngo.via and MIMneuro varied by region. When regional Z-scores were averaged into a per-patient composite measure, overall bias was near-zero, with tight limits of agreement (slope = 0.97 [95% CI 0.93-1.02], intercept = 0.11 [95% CI -0.05-0.26]), indicating minimal proportional and constant bias between platforms. Bland-Altman analysis showed small bias and narrow limits of agreement (LoA) in the low-centiloid group (mean bias -0.19, 95% LoA -0.93 to +0.55) and the greatest divergence in the intermediate group (mean bias -0.44, LoA -2.02 to +1.14). In the high-centiloid group, bias remained small (+0.16) with wider LoA (-1.92 to +2.24). Temporal cortex Deming regression demonstrated proportional and constant bias (slope = 0.70 [95% CI 0.66-0.74], intercept = 0.34 [95% CI 0.07-0.61]), indicating systematic underestimation of high Z-scores by MIM relative to Syngo.via.

CONCLUSIONS: There was overall concordance between Syngo.Via and MIMneuro quantitative amyloid PET analysis software packages, however with significant region- and amyloid burden-dependent variability that increased in the intermediate-centiloid group. These differences may influence interpretation and determination of treatment eligibility in borderline cases, emphasizing that Z-scores from different commercial platforms should not be used interchangeably without cross-validation.},
}

@article {pmid41986822,
year = {2026},
author = {Hazar-Yavuz, AN and Ertas, B and Kaya, RK and Topal, F and Kabataş, GS and Altuntaş, C and Kabasakal, L and Yazir, Y and Cam, ME},
title = {Modulation of Amyloid and Tau Pathology by Empagliflozin in a High-Fat Diet and Streptozotocin-Induced Type 2 Diabetes-Associated Alzheimer's Model.},
journal = {The European journal of neuroscience},
volume = {63},
number = {8},
pages = {e70495},
doi = {10.1111/ejn.70495},
pmid = {41986822},
issn = {1460-9568},
support = {SAG-A-110618-0292//Marmara Üniversitesi/ ; },
mesh = {Animals ; *Benzhydryl Compounds/pharmacology/therapeutic use ; *Glucosides/pharmacology/therapeutic use ; *Alzheimer Disease/metabolism/drug therapy/pathology/etiology ; Diet, High-Fat/adverse effects ; *tau Proteins/metabolism ; *Diabetes Mellitus, Type 2/complications/metabolism/drug therapy ; Male ; Rats ; *Amyloid beta-Peptides/metabolism ; *Diabetes Mellitus, Experimental/metabolism/complications/drug therapy ; *Sodium-Glucose Transporter 2 Inhibitors/pharmacology ; *Neuroprotective Agents/pharmacology ; Streptozocin ; Rivastigmine/pharmacology ; Disease Models, Animal ; Brain/metabolism/drug effects/pathology ; Rats, Wistar ; Blood Glucose/drug effects/metabolism ; },
abstract = {Type 2 diabetes mellitus (T2DM) contributes notably to the development and progression of Alzheimer's disease (AD) through overlapping pathological mechanisms such as insulin resistance, amyloid-β (Aβ) accumulation and tau hyperphosphorylation. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have recently emerged as promising candidates for neuroprotection in metabolic disorders. The present work explored the potential therapeutic impact of the SGLT2 inhibitor empagliflozin (EMPA) compared with the acetylcholinesterase inhibitor rivastigmine (RIV) in a T2DM-induced AD rat model. The T2DM-AD model was established using a high-fat diet in combination with subsequent low-dose streptozotocin (35 mg/kg) administration. Metabolic, behavioural, biochemical, molecular and histopathological parameters were assessed to evaluate disease progression and treatment efficacy. EMPA significantly improved glucose metabolism, lowered nonfasting blood glucose, enhanced oral glucose tolerance and restored insulin levels in peripheral and central tissues. EMPA ameliorated short-term and spatial memory deficits and reduced Aβ and phosphorylated tau levels in the brain, serum and pancreas and normalized acetylcholinesterase and glycogen kinase-3β expression. Histological and immunohistochemical analyses corroborated these neuroprotective effects, revealing reduced neurodegeneration and proteinopathy in the cerebral cortex and hippocampus. EMPA exerts multifaceted neuroprotective and metabolic benefits in a T2DM-induced AD model, offering a therapeutic advantage over RIV by targeting both peripheral metabolic dysfunction and central neurodegeneration. By demonstrating that modulation of systemic glucose homeostasis can directly influence amyloid and tau pathology as well as cognitive outcomes, these findings provide important insight into the metabolic-neurodegenerative interface and highlight SGLT2 inhibition as a promising strategy for diabetes-associated cognitive decline and AD within the field of neuroscience.},
}

Animals
*Benzhydryl Compounds/pharmacology/therapeutic use
*Glucosides/pharmacology/therapeutic use
*Alzheimer Disease/metabolism/drug therapy/pathology/etiology
Diet, High-Fat/adverse effects
*tau Proteins/metabolism
*Diabetes Mellitus, Type 2/complications/metabolism/drug therapy
Male
Rats
*Amyloid beta-Peptides/metabolism
*Diabetes Mellitus, Experimental/metabolism/complications/drug therapy
*Sodium-Glucose Transporter 2 Inhibitors/pharmacology
*Neuroprotective Agents/pharmacology
Streptozocin
Rivastigmine/pharmacology
Disease Models, Animal
Brain/metabolism/drug effects/pathology
Rats, Wistar
Blood Glucose/drug effects/metabolism

@article {pmid41987015,
year = {2026},
author = {Morales, MJ and Ricketts, S and Grudzen, CR and Brody, AA and Chodosh, J and Goldfeld, K and Shah, MN and , },
title = {Bridging the Gap Between the ED and Home: The Community Paramedic-Led Transitions Intervention for Persons Living With Dementia.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70403},
pmid = {41987015},
issn = {1532-5415},
support = {P30 CA008748/CA/NCI NIH HHS/United States ; U19 AG078105-01A1/AG/NIA NIH HHS/United States ; },
abstract = {More than 6 million persons living with dementia (PLWD) in the United States rely on the emergency department (ED) for unscheduled care, with up to half discharged home after treatment. The ED-to-home transition poses significant challenges for PLWD and their care partners (referred to as "dyads"), contributing to high rates of ED revisits and adverse outcomes. The Community Paramedic-led Transitions Intervention (CPTI) was developed to address these challenges by adapting the validated Care Transitions Intervention for the ED setting. Delivered by trained community paramedics, CPTI is a short-term 30-day program that includes one home visit and up to three follow-up phone calls. Using a coaching model, paramedic coaches work with members of the dyad to strengthen their knowledge, skills, and confidence to manage their health and successfully navigate the health care system. CPTI is being implemented as part of Emergency Departments LEading the Transformation of Alzheimer's and Dementia Care (ED-LEAD), a cluster-randomized pragmatic trial testing 3 interventions designed to improve outcomes for PLWD discharged home from the ED across 14 health systems and 79 EDs nationwide. This paper describes the CPTI model as implemented within ED-LEAD, detailing its theoretical foundation, structure, training curriculum, workflow integration, and implementation monitoring. This framework can provide a model for health systems, provider groups, and emergency medical service agencies interested in adopting this innovative approach and implementing the CPTI. Insights from its implementation within ED-LEAD will guide future efforts to improve post-ED outcomes and continuity of care for PLWD and their care partners.},
}

@article {pmid41987849,
year = {2026},
author = {Xu, Y and Chen, D and Ye, Q and Zhang, P and Shi, J and Li, S and Sun, Y and Zhao, Z and Tang, Y and Zhang, P and Tang, Z},
title = {Emerging Neural Recording and Neurostimulation Technologies Based on Brain-Computer Interface: A Promising Approach for Neuropsychiatric Disorders.},
journal = {MedComm},
volume = {7},
number = {},
pages = {e70739},
pmid = {41987849},
issn = {2688-2663},
abstract = {Neurological and psychiatric disorders, arising from disruptions in neural circuitry, pose a major and growing challenge to global healthcare systems. Brain-computer interface (BCI) technology has emerged as a promising approach, enabling direct communication between the brain and external devices. By facilitating bidirectional interaction with the nervous system, BCIs open new avenues for both diagnosis and treatment. In this review, we examine recent advances in recording and stimulation technologies within the BCI framework and evaluate their therapeutic potential across major neuropsychiatric disorders. We focus particularly on post-stroke motor rehabilitation as a representative paradigm, providing detailed analysis of the mechanisms, clinical evidence, and future prospects of endovascular BCI, BCI-integrated epidural spinal cord stimulation, and BCI-driven deep brain stimulation. We further extend the discussion to movement disorders such as Parkinson's disease and epilepsy, as well as cognitive and psychiatric conditions including Alzheimer's disease and depression, highlighting how BCI-based approaches enable symptom detection and closed-loop neuromodulation. Additionally, we address ethical and societal considerations accompanying clinical translation of these advanced neurotechnologies. By integrating current evidence, this review highlights a paradigm shift toward more active, precise, and personalized neural rehabilitation enabled by BCI systems, while outlining key challenges and future directions for research and clinical application.},
}

@article {pmid41987879,
year = {2026},
author = {Manganotti, P and Palacino, F and Pavan, S and Benussi, A},
title = {Epilepsy and EEG abnormalities in neurodegenerative dementias: toward a system epilepsy framework.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1806471},
pmid = {41987879},
issn = {1663-4365},
abstract = {Epilepsy and epileptiform activity represent underrecognized yet clinically significant features of neurodegenerative dementias, with emerging evidence suggesting they may contribute to disease progression rather than merely representing epiphenomena of neuronal loss. This comprehensive review examines the epidemiology, clinical presentation, electroencephalographic findings, and pathophysiological mechanisms underlying seizure activity in Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). Meta-analytic data demonstrate elevated seizure prevalence across all three conditions, with cumulative probabilities of 13.4% for AD, 14.7% for DLB, and 3.0% for FTD, representing risk elevations of approximately 6- to 10-fold compared to age-matched controls. Critically, subclinical epileptiform activity detected through prolonged electroencephalographic monitoring affects up to 42-54% of AD patients and is associated with 1.5-fold accelerated cognitive decline. Each dementia subtype exhibits characteristic electroencephalographic signatures: AD demonstrates progressive spectral slowing with predominantly left temporal epileptiform discharges; DLB shows highly characteristic slowing of the dominant rhythm below 8 Hz with high diagnostic accuracy; and FTD displays relatively preserved background activity with frontal-temporal hypoconnectivity. We synthesize evidence from transcranial magnetic stimulation studies demonstrating distinct patterns of cortical excitability alterations across these conditions, with AD showing bilateral increases in cortical excitability and reduced GABAergic and cholinergic inhibition. Building upon these observations, dementia-associated epilepsy may be conceptualized within the framework of system epilepsies, arising from dysfunction of vulnerable neural networks rather than discrete lesions. This paradigm shift has profound therapeutic implications, supporting network-targeted interventions and the potential disease-modifying role of antiseizure medications. We conclude by presenting clinical recommendations for monitoring and treatment, emphasizing the need for prolonged electroencephalographic evaluation and consideration of empirical treatment for subclinical epileptiform activity associated with cognitive fluctuations.},
}

@article {pmid41989792,
year = {2026},
author = {Upadhyay, R and Jain, A and Trivedi, K and Desavathu, M},
title = {Nanomedicines for Neurodegenerative Ageing: Nasal Delivery Innovations for Alzheimer's and Parkinson's Disease.},
journal = {Journal of drug targeting},
volume = {},
number = {},
pages = {1-40},
doi = {10.1080/1061186X.2026.2659210},
pmid = {41989792},
issn = {1029-2330},
abstract = {Alzheimer's disease and Parkinson's disease are progressive, age-related neurodegenerative disorders with increasing global prevalence, yet their treatment remains challenging despite the availability of multiple therapeutic agents. Conventional formulations are often limited by poor solubility, restricted blood-brain barrier penetration, extensive first-pass metabolism, short elimination half-life, low brain bioavailability, and systemic adverse effects. In recent years, the nose-to-brain route has emerged as a promising strategy for delivering therapeutics directly to the brain. This approach offers non-invasive administration, rapid onset of action, direct brain targeting via olfactory and trigeminal pathways, reduced systemic exposure, bypassing of first-pass metabolism, improved bioavailability, and enhanced patient compliance. To exploit these advantages, a variety of biodegradable nanocarrier systems have been investigated, including lipid-based and polymer-based nanoparticles, nasal gel-based systems, nanoemulsions, nanosuspensions, hybrid nanoparticles, and nasal sprays. This review provides a comprehensive synthesis of preclinical studies evaluating nose-to-brain nanocarrier-based delivery strategies for Alzheimer's and Parkinson's disease, with particular emphasis on their pharmacokinetic and pharmacodynamic performance. Collectively, the evidence indicates that nose-to-brain nanocarriers can effectively address key limitations of conventional therapies by enhancing brain targeting and therapeutic efficacy. However, successful clinical translation will require addressing formulation-related challenges such as mucociliary clearance, nasal irritation, burst drug release, and long-term safety, alongside well-designed clinical studies. Future research should therefore focus on exploring emerging delivery platforms to further advance nose-to-brain strategies for the management of neurodegenerative diseases.},
}

@article {pmid41989985,
year = {2026},
author = {Sun, M and Lu, Z and Chen, WM and Lv, S and Fu, N and Yang, Y and Wang, Y and Miao, M and Wu, SY and Zhang, J},
title = {N-Acetylcysteine and Dementia Risk in Elderly Patients.},
journal = {International journal of geriatric psychiatry},
volume = {41},
number = {4},
pages = {e70212},
doi = {10.1002/gps.70212},
pmid = {41989985},
issn = {1099-1166},
mesh = {Humans ; *Acetylcysteine/administration & dosage/therapeutic use ; Male ; Aged ; Female ; Taiwan/epidemiology ; *Dementia/epidemiology/prevention & control ; Aged, 80 and over ; *Pulmonary Disease, Chronic Obstructive/drug therapy/epidemiology ; Proportional Hazards Models ; Risk Factors ; Dose-Response Relationship, Drug ; Propensity Score ; },
abstract = {OBJECTIVE: This study aimed to investigate the association between N-acetylcysteine (NAC) use and dementia risk in elderly individuals diagnosed with Chronic Obstructive Pulmonary Disease (COPD).

METHODS: Utilizing Taiwan's National Health Insurance Research Database (NHIRD), we conducted a population-based cohort study of 105,144 elderly COPD patients to investigate the association between NAC use and dementia risk. Propensity score matching (PSM) ensured balanced covariates between NAC users and nonusers. Cox regression analysis and Poisson Regression analysis were employed to assess dementia risk, considering NAC dosage, treatment duration, and comorbidities. Competing risk analysis and Kaplan-Meier method were used to account for mortality risk and estimate dementia incidence, respectively.

RESULTS: Elderly NAC users demonstrated a significant association with a lower dementia risk (adjusted hazard ratio [aHR]: 0.76, 95% confidence interval [CI]: 0.74-0.78). Higher daily NAC intake was associated with a dose-dependent decline in dementia risk, with optimal benefits observed at an average daily dose of 1.61 defined daily doses (DDD). Stratification by cumulative defined daily doses (cDDD) of NAC revealed a consistent dose-response relationship, with progressively diminished dementia risk across quartiles of cDDD. Notably, NAC use was associated with a lower risk of Alzheimer's dementia (aHR: 0.68, 95% CI: 0.66-0.70) compared to non-NAC antimucolytic users.

CONCLUSIONS: NAC use is associated with a dose-dependent reduction in dementia risk among elderly COPD patients, particularly for Alzheimer's dementia. Our findings underscore the potential of NAC as a potential protective factor against dementia in this vulnerable population, warranting further investigation and consideration in clinical practice.},
}

Humans
*Acetylcysteine/administration & dosage/therapeutic use
Male
Aged
Female
Taiwan/epidemiology
*Dementia/epidemiology/prevention & control
Aged, 80 and over
*Pulmonary Disease, Chronic Obstructive/drug therapy/epidemiology
Proportional Hazards Models
Risk Factors
Dose-Response Relationship, Drug
Propensity Score

@article {pmid41990984,
year = {2026},
author = {Xu, G and Gao, J and Wang, T and Wu, H and Liu, S and Ji, Y and Wang, P and Guo, M},
title = {Differential modulation of EEG microstate spatiotemporal dynamics by rTMS and iTBS correlates with clinical improvement in Alzheimer's disease.},
journal = {Brain research},
volume = {},
number = {},
pages = {150323},
doi = {10.1016/j.brainres.2026.150323},
pmid = {41990984},
issn = {1872-6240},
abstract = {BACKGROUND: Transcranial magnetic stimulation (TMS) is an effective therapy for patients with Alzheimer's Disease (AD), potentially modulating aberrant functional connectivity. Electroencephalography (EEG) microstates represent transient large-scale resting networks and have emerged as candidate markers for AD. However, their modulation by repetitive TMS (rTMS) and intermittent theta burst stimulation (iTBS) protocols remains to be elucidated.

METHODS: Resting-state EEG was recorded from 28 AD patients at baseline and following the 1st, 7th, and 14th sessions of rTMS or iTBS treatment. Polarity-insensitive modified k-means clustering was used to segment EEGs into constituent microstates, which were then subjected to source localization to identify their corresponding cortical regions. Longitudinal changes within subjects in clinical status and microstate parameters (duration, occurrence, coverage, transition probability) were evaluated with one-way repeated-measures analysis of variance, and differences between rTMS and iTBS groups were assessed using t-tests.

RESULTS: Four microstates (MS A-D) were identified from EEG data. rTMS predominantly induced sustained suppression of MS-B, whereas iTBS elicited early-phase increases in MS-C activity. Clinical symptoms improvement following TMS correlated with increased MS-C and decreased MS-B activity. Source localization revealed rTMS predominantly modulated MS-B generators in the occipital cortex (impacting visual and dorsal attention networks), while iTBS preferentially engaged MS-C generators in the parietal cortex (affecting sensorimotor and frontoparietal networks).

CONCLUSIONS: We identified distinct EEG microstates and their underlying cortical generators associated with clinical improvement in AD following treatment with rTMS and iTBS protocols. The results demonstrate protocol-specific spatiotemporal modulation profiles and temporal dynamics, highlighting differential neural mechanisms of rTMS and iTBS.},
}

@article {pmid41991301,
year = {2026},
author = {Guo, SF and Wang, EL and Zeng, JX and Hou, YQ},
title = {[Research progress on the pathogenesis of Alzheimer's disease related to infectious pathogens].},
journal = {Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine]},
volume = {60},
number = {4},
pages = {631-639},
doi = {10.3760/cma.j.cn112150-20250607-00522},
pmid = {41991301},
issn = {0253-9624},
support = {2024ZDXK0065//Key Discipline Project of Shanghai Municipal Health Commission/ ; 24SJYXZDA06//Key Discipline Project of Shanghai Songjiang District Municipal Health Commission/ ; 23ZR1457300//Project supported by the Shanghai Committee of Science and Technology/ ; 82401655//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Alzheimer Disease/microbiology/etiology ; Blood-Brain Barrier ; },
abstract = {Alzheimer's disease (AD), one of the most prevalent neurodegenerative disorders, is clinically characterized by progressive memory decline and cognitive impairment, predominantly affecting the elderly population. The pathogenesis of AD remains incompletely elucidated, and effective curative treatments are currently lacking. Notably, China has become the country with the highest number of AD cases globally. Growing evidence suggests that infections may play a crucial role in the initiation and progression of AD, though the precise mechanisms remain unclear. This review systematically examines how infectious agents participate in AD pathogenesis through key pathways including: driving neuroinflammatory responses, disrupting the blood-brain barrier and mediating central nervous system invasion, programmed cell death, and modulating epigenetic regulation and gene expression. We focus on recent advances in understanding the associations between AD and diverse pathogens including viruses, bacteria, fungi, and parasites. Finally, we discuss current anti-infective therapeutic strategies and outline future research priorities, aiming to provide novel theoretical foundations and investigative approaches for AD prevention and treatment.},
}

Humans
*Alzheimer Disease/microbiology/etiology
Blood-Brain Barrier

@article {pmid41975524,
year = {2026},
author = {More, SA and Mundke, RN and Agrawal, YO and Awathale, SN and Goyal, SN and Nakhate, KT and Rathod, SS},
title = {Intracerebroventricular streptozotocin-induced animal model of Alzheimer's disease: revealing dose optimization, administration regimen, and molecular pathways.},
journal = {Laboratory animal research},
volume = {42},
number = {1},
pages = {},
pmid = {41975524},
issn = {1738-6055},
abstract = {UNLABELLED: Streptozotocin (STZ) is a commonly administered chemical via the intracerebroventricular (ICV) route in rodents to induce Alzheimer’s disease (AD)-like symptoms. Unfortunately, available research articles from different laboratories suggest inconsistency in doses, administration schedules, and target brain regions. For instance, ICV dose varies from 1.5 to 5 mg/kg either unilaterally or bilaterally, for 7 days to 21 days, as a single or multiple injections. Therefore, it is challenging for novice investigators to select the optimal doses, treatment durations, and targeted molecular pathways while employing STZ to induce AD-like conditions in experimental animals. In this background, the information related to the STZ-induced animal model of AD should be available on a single platform to aid researchers in selecting the suitable doses and regimens that suit their research objectives. The literature search was carried out by employing search engines such as PubMed and Google Scholar with keywords such as streptozotocin, intracerebroventricular, dosage optimization, Alzheimer’s disease, neuroinflammation, and oxidative stress. The present review highlights the articles published up to May 2025, with predefined inclusion (ICV-STZ model, cognitive/biochemical outcomes) and exclusion criteria (non-peer-reviewed papers, studies lacking behavioral or molecular endpoints, and studies older than 20 years). We have attempted to present the optimal dose, administration regimen, and biological process for inducing ICV-STZ AD models based on their advantages and limitations. According to the comparative quantitative evaluation of preclinical investigations, bilateral ICV administration of STZ at a cumulative dose of 3 mg/kg (1.5 mg/kg on days 1 and 3) displays the most reliable and physiologically relevant regimen. Studies also demonstrated that between 14 and 21 days after injection, this regimen reliably causes oxidative stress, neuroinflammation, cholinergic dysfunction, and progressive cognitive impairments, offering a balanced picture of physiological, histological, and behavioral alterations. However, unlike transgenic models, the ICV-STZ paradigm generally fails to develop extensive amyloid-beta plaque deposition or well-formed neurofibrillary tangles. Hence, more quantitative investigations are necessary to validate this optimization.

GRAPHICAL ABSTRACT: [Image: see text]},
}

@article {pmid41981211,
year = {2026},
author = {Zhu, TT and Liu, PM and Hashimoto, K and Yang, JJ},
title = {Clinical innovations and future directions of nanoparticles in the treatment of psychiatric and neurological disorders.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41981211},
issn = {1476-5578},
support = {82171189//National Natural Science Foundation of China (National Science Foundation of China)/ ; 81971020//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Nanoparticles (NPs) provide a versatile toolkit for psychiatry and neurology by leveraging tunable size, surface chemistry, and payload control to overcome long-standing barriers in central nervous system (CNS) therapy. Lipid, polymeric, inorganic, and hybrid NPs can be engineered to traverse the blood-brain barrier (BBB) via receptor/transporter pathways, target specific cell types, and deliver sustained or stimuli-responsive release. Beyond drug delivery, NPs improve imaging, enable gene/RNA therapeutics, and support anti-inflammatory and neuroprotective strategies, advancing precision medicine. Preclinical studies in depression, schizophrenia, Alzheimer's disease, and Parkinson's disease show superior exposure, target engagement, and behavioral or cognitive benefits versus free drugs, including photothermal/photodynamic and nanobody-based approaches. Clinically, translation remains early: a handful of CNS-directed candidates (e.g., gold-based bioenergetic agents, intranasal lipid formulations, liposomal modulators) are in trials, while approvals largely lie outside CNS indications. Key hurdles include variable BBB integrity, immunogenicity and protein-corona effects, manufacturing and stability constraints, and limited effect-site exposure-response data in humans. This review outlines a translational playbook: model-informed development linking formulation to brain interstitial exposure; Quality-by-Design chemistry, manufacturing, and controls (CMC); stratified, adaptive trials with population PK/PD and harmonized biomarkers; and proactive safety monitoring with long-term registries. We also highlight NP strategies targeting the gut-brain axis-delivering probiotics, metabolites, or antimicrobials-as complementary routes to modulate neuroinflammation and circuit function. With rigorous clinical science, manufacturing quality, and safety governance embedded from the outset, nanotechnology is positioned to deliver safer, more effective, and potentially disease-modifying therapies for CNS disorders.},
}

@article {pmid41981256,
year = {2026},
author = {Shao, B and Zeng, Y and Ju, J},
title = {Dynamic collaboration between mitochondria and organelles: mechanisms, functions, and disease implications.},
journal = {Apoptosis : an international journal on programmed cell death},
volume = {31},
number = {4},
pages = {},
pmid = {41981256},
issn = {1573-675X},
support = {32572715//The National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Mitochondria/metabolism ; Neurodegenerative Diseases/metabolism/pathology ; Neoplasms/metabolism/pathology/genetics ; Animals ; *Organelles/metabolism ; Alzheimer Disease/metabolism ; Endoplasmic Reticulum/metabolism ; Oxidative Stress ; },
abstract = {In recent years, numerous studies have revealed that dysregulation of mitochondria-organelle interactions is a common feature underlying various pathological processes and pathogen infections. For instance, in Alzheimer's disease (AD), dysfunction of mitochondrial-associated ER membranes (MAMs) leads to calcium overload and oxidative stress, while cancer cells enhance glycolysis by remodeling mitochondria-Golgi interactions. Targeting these key interacting nodes has shown significant therapeutic potential. Although technological advances have uncovered some underlying mechanisms, the spatiotemporal dynamics, tissue specificity, and causal role of organelle interactions in diseases remain unclear. In-depth understanding of these collaborative networks will provide new targets for the treatment of cancer, metabolic syndrome, and neurodegenerative diseases, and also create novel possibilities for elucidating pathogen-host interaction mechanisms and developing anti-infective therapies. Given the importance of dynamic mitochondria-organelle collaboration in disease treatment, this review first focuses on analyzing the molecular mechanisms underlying this crosstalk. Building on this, the dysregulation of mitochondria-organelle collaboration in diseases is discussed in depth, with a particular focus on cancer, cardiovascular diseases, metabolic syndrome, and neurodegenerative diseases. Finally, the potential therapeutic strategies targeting organelle interactions are summarized and analyzed. In conclusion, the information in this manuscript offers a new way to think about and treat several serious illnesses.},
}

Humans
*Mitochondria/metabolism
Neurodegenerative Diseases/metabolism/pathology
Neoplasms/metabolism/pathology/genetics
Animals
*Organelles/metabolism
Alzheimer Disease/metabolism
Endoplasmic Reticulum/metabolism
Oxidative Stress

@article {pmid41981347,
year = {2026},
author = {Sengupta, P and Mukhopadhyay, D},
title = {Nuclear Translocation of IGF1R Induces Cell Cycle Re-entry via Cyclin D1 Regulation in an Aβ-Driven Alzheimer's Disease Model.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {41981347},
issn = {1559-1182},
mesh = {*Alzheimer Disease/metabolism/pathology/genetics ; Humans ; *Amyloid beta-Peptides/toxicity ; *Cell Nucleus/metabolism/drug effects ; *Receptor, IGF Type 1/metabolism ; *Cyclin D1/metabolism ; Cell Line, Tumor ; *Cell Cycle/drug effects ; Active Transport, Cell Nucleus/drug effects ; Phosphorylation/drug effects ; Neurons/metabolism/drug effects ; Models, Biological ; Protein Transport/drug effects ; },
abstract = {Alzheimer's disease (AD) involves progressive neurodegeneration, with abnormal receptor signaling and disrupted cell-cycle activity leading to neuronal loss. Here, we identify a previously unknown mechanism linking β-amyloid (Aβ) exposure to the nuclear translocation of the Insulin-like Growth Factor 1 Receptor (IGF1R) in differentiated SH-SY5Y neuronal cells. The differentiated cholinergic model induced by retinoic acid and BDNF expresses acetylcholinesterase (AChE) and indicates that under amyloidogenic stress, IGF1R may transition from homeostatic membrane and vesicular signaling to a nuclear-centric function. We show that prolonged Aβ treatment causes phosphorylation-dependent nuclear import of IGF1R, confirmed by confocal imaging and biochemical fractionation. IGF1R is conventionally located in the membrane and vesicular membranes; however, under amyloidogenic stress, we show here that it is imported to the nucleus and exerts transcriptional control. The buildup of nuclear IGF1R coincided with increased Cyclin D1 levels and redistribution of neurons into S and G2 phases, indicating abnormal cell-cycle re-entry. Chromatin immunoprecipitation demonstrated increased IGF1R binding at the CCND1 and JUN promoters after Aβ exposure, suggesting a direct role in gene transcription. Pharmacological blockade of IGF1R phosphorylation by PPP or SUMOylation by Ginkgolic acid significantly reduced Cyclin D1 elevation, implying that both post-translational modifications are involved in receptor nuclear trafficking. Co-immunoprecipitation and confocal imaging identified Nucleophosmin (NPM1) as a putative IGF1R interacting partner, potentially contributing to its nuclear transport and stabilizing receptor-chromatin complexes. These results establish IGF1R as a signaling-transcription connector linking extracellular amyloid stress to nuclear gene regulation, providing a mechanistic explanation for faulty neuronal cell-cycle re-entry in AD. We suggest that abnormal IGF1R-NPM1 interactions contribute to receptor mislocalization and cell-cycle failure, highlighting new targets for therapeutic intervention aimed at receptor trafficking and neuroprotection in Alzheimer's disease.},
}

*Alzheimer Disease/metabolism/pathology/genetics
Humans
*Amyloid beta-Peptides/toxicity
*Cell Nucleus/metabolism/drug effects
*Receptor, IGF Type 1/metabolism
*Cyclin D1/metabolism
Cell Line, Tumor
*Cell Cycle/drug effects
Active Transport, Cell Nucleus/drug effects
Phosphorylation/drug effects
Neurons/metabolism/drug effects
Models, Biological
Protein Transport/drug effects

@article {pmid41982209,
year = {2026},
author = {Ubuka, T and Yuyama, K and Genjima, A and Nagakura, M and Kato, K and Hayashi, S and Makino, N and Yamane, T and Hirose, T and Yamane, Y},
title = {Mitigating cognitive decline in Alzheimer's disease dementia by enhancing cognitive reserve through neuroplasticity in addition to amyloid-β reduction.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1769431},
pmid = {41982209},
issn = {1663-4365},
}

@article {pmid41984492,
year = {2026},
author = {Chiu, PY and Chiu, HJ and Wei, CY and Tzeng, RC and Chang, HT and Chen, HM},
title = {Dementia with Lewy bodies clinical syndrome (DLBCS) questionnaire: A simple tool for the clinical screening of DLB.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261441187},
doi = {10.1177/13872877261441187},
pmid = {41984492},
issn = {1875-8908},
abstract = {BackgroundDementia with Lewy bodies (DLB) remains underdiagnosed due to overlapping clinical features with Alzheimer's disease (AD) and vascular cognitive impairment (VCI). Early recognition is crucial, as DLB has distinct prognostic and therapeutic implications.ObjectiveThis study aimed to develop and validate a brief, clinically applicable screening instrument to improve bedside recognition of DLB and to compare its performance with established diagnostic approaches.MethodsWe designed the Dementia with Lewy Bodies Clinical Screening Questionnaire (DLBCSQ) and an extended version (DLBCSQ11) incorporating additional items to differentiate DLB from VCI. Clinical data were collected from a dementia registry in Taiwan, including patients with AD, VCI, and DLB. The diagnostic accuracy of DLBCSQ versions was evaluated using receiver operating characteristic (ROC) analyses across subgroups, including mild cognitive impairment with Lewy bodies (LB-MCI).ResultsBoth DLBCSQ and DLBCSQ11 demonstrated strong discriminatory ability, with area under the curve (AUC) values exceeding 0.84 for differentiating DLB from non-DLB syndromes. DLBCSQ11 showed greater specificity for distinguishing DLB from VCI, though about 20% of VCI patients still exhibited DLB-like features. Supplementary questions on visual hallucinations and tremors further improved detection of prodromal or mixed DLB cases.ConclusionsThe DLBCSQ9 and DLBCSQ11 represent practical and effective tools for clinical and bedside identification of DLB. By improving early recognition and differentiation from AD and VCI, these instruments may facilitate timely diagnosis, guide treatment decisions, and support future research on mixed dementia syndromes.},
}

@article {pmid41984500,
year = {2026},
author = {Shah, S and Tran, T and Wadhwa, SS and Huerta, GI and Ovalle-Eliseo, S and Martinez, A and Vossel, K and Campos, B and Bholat, M and Moreno, G and Diaz-Santos, M and Chang, TS},
title = {Increased dementia diagnosis and workup in primary care with a bilingual screening tool integrated in the electronic health record.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261441776},
doi = {10.1177/13872877261441776},
pmid = {41984500},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) affects over 10% of adults aged 65 and older. Black and Hispanic/Latino individuals experience 1.5-2.0 times higher prevalence than White individuals, yet AD remains underdiagnosed, particularly in non-White populations. Common screening tools such as the Mini-Mental State Examination and Montreal Cognitive Assessment are limited by time burden and cultural sensitivity.ObjectiveTo evaluate the impact of integrating a brief dementia screening tool (DST) into the electronic health record (EHR) on diagnosis, evaluation, and treatment in primary care.MethodsThe DST, developed by the University of California Alzheimer's Disease Centers and the California Department of Public Health, takes under five minutes and includes a three-question patient form, optional informant questionnaire, and Mini-Cog. It was translated and culturally adapted for Spanish-speaking patients and embedded in the EHR. Patients aged ≥60 in a diverse Los Angeles County family medicine clinic completed the DST before annual wellness visits. We conducted a pre-post study comparing patients without prior dementia diagnoses during pre-intervention (February 2021-August 2022) and post-intervention (January 2023-June 2024) periods. Primary outcome was new dementia diagnosis; secondary outcomes included medications, referrals, labs, and imaging.ResultsAmong 1515 eligible patients post-intervention, 1249 completed screening. New dementia diagnoses increased from 0.75% pre-DST to 2.45% among those screening positive (adjusted OR 2.99; p = 0.01). Dementia medications, laboratory orders, and specialty referrals significantly increased; imaging did not.ConclusionsA brief, culturally adapted DST integrated into primary care improved dementia diagnosis, evaluation, and treatment.},
}

@article {pmid41984564,
year = {2026},
author = {Shavlovskaya, OA},
title = {[The effectiveness of citicoline in the treatment of cognitive disorders].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {3},
pages = {136-140},
doi = {10.17116/jnevro2026126031136},
pmid = {41984564},
issn = {1997-7298},
mesh = {Humans ; *Cytidine Diphosphate Choline/therapeutic use ; *Nootropic Agents/therapeutic use ; Parkinson Disease/drug therapy/complications ; *Cognitive Dysfunction/drug therapy ; Alzheimer Disease/drug therapy ; Randomized Controlled Trials as Topic ; Treatment Outcome ; Stroke/complications ; },
abstract = {Randomized controlled trials, systematic reviews, and meta-analyses have shown that citicoline is highly effective in the treatment of vascular cognitive impairments (CI) of various origins (post-stroke, chronic cerebral ischemia (CCI)), post-traumatic CI, mild CI in neurodegenerative diseases (Alzheimer's disease, Parkinson's disease), and in patients with age-related memory impairments. Citicoline administration regimens: 1) post-stroke CI at a dose of 1000 mg/day. for a course of 4-12 months; 2) mild CI of vascular origin at a dose of 500 mg/day for a course of 3-9 months; 3) CI against the background of CCI at a dose of 500-2000 mg, the duration of the course depends on the severity of the symptoms; 4) non-demented CI at a dose of 1000 mg/day course of 9 months; 5) mild CI against Parkinson's disease at a dose of 1000 mg/day 12-18 months.},
}

Humans
*Cytidine Diphosphate Choline/therapeutic use
*Nootropic Agents/therapeutic use
Parkinson Disease/drug therapy/complications
*Cognitive Dysfunction/drug therapy
Alzheimer Disease/drug therapy
Randomized Controlled Trials as Topic
Treatment Outcome
Stroke/complications

@article {pmid41985059,
year = {2026},
author = {Du, JH and Shen, M and Mathys, H and Roeder, K},
title = {Uncovering causal relationships in single-cell omic studies with causarray.},
journal = {Briefings in bioinformatics},
volume = {27},
number = {2},
pages = {},
doi = {10.1093/bib/bbag175},
pmid = {41985059},
issn = {1477-4054},
mesh = {*Single-Cell Analysis/methods ; Humans ; Animals ; Mice ; Alzheimer Disease/genetics ; *Genomics/methods ; Brain/metabolism ; Autistic Disorder/genetics ; Machine Learning ; Transcriptome ; Case-Control Studies ; },
abstract = {Advances in single-cell sequencing and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technologies have enabled detailed case-control comparisons and experimental perturbations at single-cell resolution. However, uncovering causal relationships in observational genomic data remains challenging due to selection bias and inadequate adjustment for unmeasured confounders, particularly in heterogeneous datasets. To address these challenges, we introduce causarray, a robust causal inference framework for analyzing array-based genomic data at both pseudo-bulk and single-cell levels under unmeasured confounding. causarray integrates a generalized confounder adjustment method to account for unmeasured confounders and employs semiparametric inference with flexible machine learning techniques to ensure robust statistical estimation of treatment effects. Benchmarking results show that causarray robustly separates treatment effects from confounders while preserving biological signals across diverse settings. We also apply causarray to two single-cell genomic studies: (i) an in vivo Perturb-seq study of autism risk genes in developing mouse brains and (ii) a case-control study of Alzheimer's disease (AD) using three human brain transcriptomic datasets. In these applications, causarray identifies clustered causal effects of multiple autism risk genes and consistent causally affected genes across AD datasets, uncovering biologically relevant pathways directly linked to neuronal development and synaptic functions that are critical for understanding disease pathology.},
}

*Single-Cell Analysis/methods
Humans
Animals
Mice
Alzheimer Disease/genetics
*Genomics/methods
Brain/metabolism
Autistic Disorder/genetics
Machine Learning
Transcriptome
Case-Control Studies

@article {pmid41973126,
year = {2026},
author = {Shinde, P and Sathiyanarayanan, A and Lohidasan, S},
title = {Exploration of potential neuroprotective agents from medicinal plants for the treatment of Alzheimer's disease-approach through in silico ADMET, network pharmacology, docking, and dynamics studies.},
journal = {Journal of molecular modeling},
volume = {32},
number = {5},
pages = {},
pmid = {41973126},
issn = {0948-5023},
mesh = {*Alzheimer Disease/drug therapy ; *Molecular Docking Simulation ; *Neuroprotective Agents/chemistry/pharmacology/pharmacokinetics/therapeutic use ; Molecular Dynamics Simulation ; Network Pharmacology ; Humans ; *Plants, Medicinal/chemistry ; *Phytochemicals/chemistry/pharmacology/pharmacokinetics ; },
abstract = {CONTEXT: A degenerative brain disorder that causes memory loss is Alzheimer's disease (AD). Phytoconstituents represent a promising therapeutic strategy due to their diverse bioactivities and favourable safety profiles. This study aimed to identify potential neuroprotective phytoconstituents for AD by pharmacokinetic screening, network pharmacology, molecular docking and molecular dynamics simulation. Among 22 phytoconstituents analysed, the network revealed GSK3β, STAT3, MAOB, ESR1, and PTGS2 as key AD-associated targets. Docking results were supported by dynamic stability analysis. The combined computational results support rosmariquinone as a potential neuroprotective lead compound for AD treatment.

METHODS: Pharmacokinetic and toxicity profiling of 22 phytoconstituents was performed using Swiss ADME and ProTox III software. Target prediction and construction of the phytoconstituent-disease target-gene interaction network were conducted using Swiss Target Prediction, Gene Card and Cytoscape. Pathway enrichment was evaluated via KEGG and GO analysis. Molecular docking of all shortlisted phytoconstituents against AD-related targets was carried out using AutoDock Vina, while 500 ns molecular dynamics simulations were performed using the Desmond module of the Schrödinger Suite to assess complex stability, RMSD, RMSF and hydrogen-bond fluctuation.},
}

*Alzheimer Disease/drug therapy
*Molecular Docking Simulation
*Neuroprotective Agents/chemistry/pharmacology/pharmacokinetics/therapeutic use
Molecular Dynamics Simulation
Network Pharmacology
Humans
*Plants, Medicinal/chemistry
*Phytochemicals/chemistry/pharmacology/pharmacokinetics

@article {pmid41973520,
year = {2026},
author = {Franco Rocha, OY and Janelsins, MC and Magnuson, A},
title = {Decision-making and treatment planning for older adults with pre-existing cognitive impairment and cancer.},
journal = {Current opinion in supportive and palliative care},
volume = {},
number = {},
pages = {},
doi = {10.1097/SPC.0000000000000804},
pmid = {41973520},
issn = {1751-4266},
abstract = {PURPOSE OF REVIEW: The review aims to synthesize the current evidence on decision-making and cancer treatment planning for older adults with pre-existing cognitive impairment, Alzheimer's disease, and other related dementias.

RECENT FINDINGS: Current decision-making practices are not standardized, and evidence suggests that oncology physicians conduct burden-benefit analyses to guide treatment planning. There was a consensus on the importance of involving caregivers into the decision-making process. However, caregivers experience feelings of anxiety, uncertainty, and extra burden when deciding between treatment options and providing care. Nursing home staffs were frequently excluded from the decision-making process and were perceived as unprepared to identify and manage cancer symptoms. The planning and provision of care for this population can be guided by a comprehensive geriatric assessment (CGA). CGA can inform the decision-making process based on the patient's functionality and caregiver's resources, facilitate management of cancer care, guide the identification and management of cancer symptoms, and assist communication with patients and their caregivers.

SUMMARY: Decision-making and treatment planning for older adults with cancer and pre-existing cognitive impairment lacks standardization. CGA offers a standardized approach to guide treatment decisions, manage symptoms, and coordinate care by highlighting the needs and resources of patients and caregivers.},
}

@article {pmid41974642,
year = {2026},
author = {Xing, L and Liu, A and Gao, W and Li, J and Yao, M and Song, J and Duan, P and Li, H},
title = {Beyond the neuron: Exosomes as intercellular modulators of mitochondrial networks in the pathogenesis and treatment of Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71330},
doi = {10.1002/alz.71330},
pmid = {41974642},
issn = {1552-5279},
support = {82105035//National Natural Science Foundation of China/ ; LH2023H064//Nature Science Foundation of Heilongjiang Province/ ; ZHY2024-304//Research Project of the Traditional Chinese Medicine Administration of Heilongjiang Province/ ; },
mesh = {Humans ; *Exosomes/metabolism ; *Alzheimer Disease/metabolism/therapy/pathology ; *Mitochondria/metabolism ; *Neurons/metabolism ; Animals ; Autophagy/physiology ; },
abstract = {Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by β-amyloid deposition, hyperphosphorylated tau protein, and progressive neuronal loss. Mitochondria form a dynamic interconnected network within the central nervous system, and their dysfunction plays a central role in AD, involving oxidative stress, kinetic dysregulation, and impaired mitochondrial autophagy. As key mediators of intercellular communication, exosomes carry bioactive components that regulate mitochondrial function in recipient cells. This review summarizes advances in research on exosomes as coordinators of the mitochondrial network in the central nervous system, regulating mitochondrial quality control across different neuronal cell types. It systematically outlines the molecular mechanisms by which exosomes modulate mitochondrial function in AD through regulating mitochondrial biogenesis, fusion-fission dynamics, mitochondrial autophagy, and related signaling pathways. Furthermore, it explores the potential of engineered exosome-based targeted therapies for AD intervention, aiming to provide a theoretical foundation and research direction for developing novel therapeutic strategies targeting mitochondrial dysfunction.},
}

Humans
*Exosomes/metabolism
*Alzheimer Disease/metabolism/therapy/pathology
*Mitochondria/metabolism
*Neurons/metabolism
Animals
Autophagy/physiology

@article {pmid41975594,
year = {2026},
author = {Xu, L and Cheng, G and Hu, F and Duan, T and Han, M and Meng, H and Sun, Y and Zeng, D and Zheng, W and Yang, X and Wang, X and Tan, W and Zeng, Y},
title = {Molecular subtypes of the Alzheimer's disease spectrum: Multimodal biomarker integration, mechanistic validation, and adaptive clinical translation.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00911},
pmid = {41975594},
issn = {1673-5374},
abstract = {Alzheimer's disease exhibits considerable heterogeneity in its clinical progression, neuropathological features, and underlying etiological mechanisms. However, current clinical diagnosis and treatment primarily rely on positron emission tomography and evidence-based cerebrospinal fluid biomarkers, with less emphasis on molecular subtypes, thereby limiting meaningful subtype stratification and personalized therapeutic interventions. Given advances in large-scale multi-omics technologies, single-cell genomics, and molecular imaging, research on the molecular subtypes of Alzheimer's disease is gradually increasing. In this review, we evaluate the growing body of studies on molecular subtypes of Alzheimer's disease through a comparative analysis of multimodal biomarkers, including cerebrospinal fluid proteomic profiles, single-nucleus transcriptomic architectures, neuroimaging endophenotypes, and adaptive clinical translation. We also analyze phenotypic variations across the Alzheimer's disease continuum to bridge molecular discoveries with clinical manifestations. Findings include proteomics-driven investigations that have identified five distinct cerebrospinal fluid proteomic subtypes. These subtypes are associated with divergent genetic backgrounds, survival rates, and cortical atrophy patterns, and are mechanistically linked to aberrant neuronal hyperproliferation, dysregulated innate immune activation, abnormalities in RNA splicing and processing, choroid plexus dysfunction, and blood-brain barrier impairment. Parallel progress in single-cell technologies, such as single-nucleus RNA sequencing, single-cell ATAC sequencing, and single-cell RNA sequencing applied to postmortem brain tissues, has enabled precise mapping of pathological cellular states across various brain regions. These approaches have revealed that molecular alterations in Alzheimer's disease exhibit high cell-type specificity and have uncovered novel disease-associated vascular-glial-neuronal co-expression modules, as well as vasculature-specific mechanisms correlated with APOE4 genetic risk. Tau- positron emission tomography neuroimaging studies have delineated four distinct spatiotemporal trajectories of tau accumulation, including temporo-lateral, occipital, hippocampal-sparing, and limbic subtypes, each associated with unique clinical phenotypes. From a genetic perspective, large-scale genome-wide association studies have identified approximately 75 risk loci implicated in Alzheimer's disease pathogenesis, including 42 previously unreported genomic regions, highlighting biological processes such as microglial activation, lipid metabolism, and synaptic function. Multi-omics analyses have further defined three hierarchical subtypes of Alzheimer's disease, which are primarily distinguished by dysregulation in either metabolic pathways, astroglial activation, or vascular and leptomeningeal function. Despite these advances in delineating heterogeneity, the field continues to face significant challenges. Key among these are the lack of cross-cohort reproducibility, standardized subtyping criteria, and evidence-based clinical validation.},
}

@article {pmid41975601,
year = {2026},
author = {Wei, L and Ren, H and Lin, Y and Sun, J and Nie, S and Gao, X and Huang, Y},
title = {Cultivation and transplantation of engineered stem cells: A new strategy for promoting repair of central nervous system injury.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-01121},
pmid = {41975601},
issn = {1673-5374},
abstract = {Due to the complex pathological microenvironment of nerve injury, the ability for self-repair is extremely limited, posing a major challenge for clinical treatment. Stem cell therapy has brought hope for nerve regeneration; however, natural stem cells have limitations such as low survival rates, poor directional differentiation efficiency, and insufficient secretion of neurotrophic factors. In recent years, the development of engineered stem cells through gene editing, biomaterial co-culture, or pretreatment has emerged as a promising new strategy. This review systematically describes the current application status of engineered stem cells in the repair of nerve injury. It summarizes the pathological mechanisms of nerve injury and the biological processes of endogenous neurogenesis and regeneration, providing a theoretical basis for engineering interventions. It details the engineering strategies used, including engineering methods, cell sources, cell processing technologies, cell delivery vehicles, and cell function regulation. Additionally, it discusses the multiple mechanisms of engineered stem cells, highlighting that their therapeutic effect is not solely dependent on differentiation into neurons or glial cells for replacement. Instead, their therapeutic effects primarily arise from the strong paracrine effects of engineered stem cells: they secrete neurotrophic factors to support the survival of host neurons, regulate the immune microenvironment, release exosomes to deliver repair-related miRNA or proteins, and promote angiogenesis and axon myelination, thereby facilitating the reconstruction of neural circuits. This review provides insights into the application of engineered stem cells in preclinical research, highlighting significant functional improvements in various neurological disease models such as spinal cord injury, stroke, Alzheimer's disease, and Parkinson's disease. Finally, this paper discusses the key challenges facing the clinical translation of this technology, including the risks of tumorigenicity, the long-term survival and safety of transplanted cells, the need for standardized preparation processes, and ethical and regulatory considerations. In summary, engineered stem cells demonstrate therapeutic potential beyond that of natural stem cells through synergistic multi-mechanism effects, providing more precise and efficient strategies for nerve injury repair. This review not only outlines the technological systems and theoretical advancements in this field but also establishes an important academic foundation for promoting the transition from basic research to clinical application. It systematically summarizes the mechanisms and applications of engineered stem cells in neural repair, emphasizing their potential and existing bottlenecks in translational medicine, thus providing a theoretical basis and directional guidance for future research.},
}

@article {pmid41975605,
year = {2026},
author = {Luo, L and Yan, T and Liu, W and Gao, Y and Tang, X and Yang, L and Zhao, M},
title = {Homoplantaginin regulates various pharmacological pathways: Candidate drugs for multi-target relief of cognitive decline and pathological changes in Alzheimer's disease.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00660},
pmid = {41975605},
issn = {1673-5374},
abstract = {Alzheimer's disease is an age-associated neurodegenerative disorder with a complex pathogenesis. As a result, multi-target drug strategies have emerged in the development of anti- Alzheimer's disease medications. Natural compounds exhibit various pharmacological effects and low toxicity, making them beneficial for multifaceted intervention. Considering that NOD-like receptor protein 3 inflammasome-mediated inflammation is crucial for the treatment of Alzheimer's disease, we identified natural NOD-like receptor protein 3 inhibitors using molecular docking and a lipopolysaccharide/adenosine triphosphate-induced J774A.1 cell inflammation model. We found that homoplantaginin stably bound to NOD-like receptor protein 3, and surface plasmon resonance experiments further demonstrated that its binding affinity was 86.30 μM. Moreover, homoplantaginin effectively inhibited inflammation mediated by NOD-like receptor protein 3 inflammasome activation in J774A.1 cells by reducing the levels of interleukin-1β, interleukin-18, mature interleukin-1β (p17), and active caspase-1 (p20). Additionally, homoplantaginin treatment inhibited apoptosis and oxidative damage in L-glutamate-induced PC12 cells, as well as in aluminum chloride and D-galactose-induced Alzheimer's disease mice. The effects of homoplantaginin on Alzheimer's disease-like behavioral impairments were evaluated using the open field test, Y-maze, and Morris water maze. Results showed that there was no effect on control mice after administration of homoplantaginin once daily for 30 consecutive days, while locomotor and cognitive impairments in Alzheimer's disease mice were significantly alleviated, exhibiting superior efficacy compared with the positive drug donepezil. Importantly, consistent with the observations in J774A.1 cells, homoplantaginin inhibited the activation of the NOD-like receptor protein 3 inflammasome in the serum and brain tissues of Alzheimer's disease mice. NOD-like receptor protein 3 knockout hindered the improvement effect of homoplantaginin on cognitive deficits in Alzheimer's disease zebrafish induced by AlCl3 and D-gal, indicating that homoplantaginin enhances cognitive function by inhibiting activation of NOD-like receptor protein 3. Furthermore, homoplantaginin treatment reduced amyloid-beta deposition, oxidative stress, and apoptosis in Alzheimer's disease mice. Notably, aging is a major risk factor for Alzheimer's disease, and homoplantaginin prevented cellular senescence by regulating related biomarker levels in Alzheimer's disease mice. These results demonstrate that homoplantaginin may serve as a promising multifunctional candidate for the treatment of Alzheimer's disease.},
}

@article {pmid41975609,
year = {2026},
author = {Cao, K and Xie, J and Liang, X and Li, Y and Gong, H and Luo, H},
title = {Dendritic mesoporous silica nanoparticle-based nasal delivery carriers for passive immunotherapy of Alzheimer's disease.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00917},
pmid = {41975609},
issn = {1673-5374},
abstract = {Hyperphosphorylation of tau is a key pathological hallmark of Alzheimer's disease and is closely associated with cognitive impairment. Passive immunotherapy targeting hyperphosphorylated tau is a promising approach to inhibit tau pathology. However, the blood-brain barrier restricts antibodies from reaching the central nervous system and exerting their therapeutic effects. Here, we developed an intranasal biomacromolecule delivery strategy for the treatment of Alzheimer's disease using dendritic mesoporous silica nanoparticles modified with hyaluronic acid as a drug carrier. Ten-month-old C57BL/6J mice, htau mice, and 5×FAD mice were intranasally administered 100 μg of hyaluronic acid-dendritic mesoporous silica nanoparticles@4B1 (antibody dose), and brain tissues were collected to evaluate antibody delivery efficiency. Using this delivery system, the anti-p-tau396,404 antibody 4B1 was efficiently delivered to the brains of 5×FAD mice, with an enrichment of 7.31% ± 0.18% ID/g. Entry of the 4B1 antibody into the brain ameliorated tauopathy in Alzheimer's disease model mice, reduced neuronal loss and neuroinflammation caused by tau pathology, and reversed cognitive dysfunction. These findings suggest that the nasal delivery strategy based on hyaluronic acid-responsive release is an effective method for delivering antibody biomacromolecules to the central nervous system, showing high efficiency of antibody entry into brain tissue and intracellular delivery. Our findings also demonstrate the role of p-tau396,404 in passive immunotherapy for Alzheimer's disease, suggesting that immunotherapy targeting p-tau396,404 is a promising strategy for ameliorating Alzheimer's disease pathology, inhibiting the aggregation of hyperphosphorylated tau, and alleviating neurological damage and cognitive dysfunction.},
}

@article {pmid41975618,
year = {2026},
author = {Chen, S and Li, J and Zhou, J and Xie, W and Li, H and Yang, L and Chen, G and Long, C},
title = {NeuroD1 gene therapy converts reactive astrocytes to functional new neurons in a mouse model of Alzheimer's disease.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00721},
pmid = {41975618},
issn = {1673-5374},
abstract = {Alzheimer's disease is characterized by the presence of amyloid-beta plaques, neurofibrillary tangles, and chronic neuroinflammation. Effective therapies capable of restoring neuronal loss, a key pathological feature of Alzheimer's disease are lacking. Our previous studies have demonstrated that overexpression of neuronal differentiation 1 (NeuroD1) in astrocytes can convert astrocytes into neurons in Alzheimer's disease models and this astrocyte-to-neuron conversion technology can rescue pathological features in models of stroke and epilepsy. This study investigated whether NeuroD1-mediated in vivo reprogramming of reactive astrocytes into functional neurons could rescue neurodegeneration and cognitive decline in amyloid precursor protein/presenilin 1 transgenic Alzheimer's disease model mice. Using retro-orbital delivery of AAV-PHP.eB-GFAP-NeuroD1-GFP, we achieved broad astrocyte-to-neuron conversion throughout the brain of 7-month-old Alzheimer's disease mice. Three months post-treatment, immunostaining revealed significant neuronal regeneration in the cortex and hippocampus, accompanied by a marked reduction in neuroinflammatory markers. The converted neurons exhibited mature electrophysiological properties, including action potentials and synaptic activity, which correlated with increased neuronal density in the hippocampus. Morris water maze test demonstrated that NeuroD1-treated mice exhibited restored spatial learning and memory compared with control animals. These findings demonstrate that NeuroD1-driven neuroregeneration via gene therapy not only replenishes neuronal populations but also reduces key pathological features related to Alzheimer's disease, including neuroinflammation and amyloid plaque burden, ultimately reducing cognitive impairment. Our findings highlight in vivo astrocyte-to-neuron reprogramming through systemic astrocyte-to-neuron delivery as a promising and transformative strategy for treating Alzheimer's disease and related neurodegenerative disorders.},
}

@article {pmid41977320,
year = {2026},
author = {Toledano-Pinedo, M and Porro-Pérez, A and Schäker-Hübner, L and Diez-Iriepa, D and Iriepa, I and Siwek, A and Wolak, M and Satała, G and Bojarski, AJ and Doroz-Płonka, A and Handzlik, J and Godyń, J and Dallemagne, P and Rochais, C and Davis, A and Since, M and Pérez, B and Bellver-Sanchis, A and Irisarri, A and Pallàs, M and Solana-Manrique, C and López-Muñoz, F and Ismaili, L and Griñán-Ferré, C and Paricio, N and K Hansen, F and Więckowska, A and Marco-Contelles, J},
title = {Polyfunctionalized N-Arylsulfonyl Indoles: Identification of (E)-N-Hydroxy-3-{3-[(5-(3-(piperidin-1-yl)propoxy]-1H-indol-1-yl)sulfonyl]phenyl}a
crylamide (MTP150) for the Epigenetic-Based Therapy of Parkinson's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {7},
pages = {},
doi = {10.3390/ijms27073135},
pmid = {41977320},
issn = {1422-0067},
support = {PID2019-105813RB-C21//AEI (Government of Spain/ ; },
mesh = {Animals ; *Parkinson Disease/drug therapy/genetics/metabolism ; *Indoles/pharmacology/chemistry/therapeutic use ; Disease Models, Animal ; Caenorhabditis elegans/drug effects/genetics ; Humans ; *Neuroprotective Agents/pharmacology/chemistry ; *Epigenesis, Genetic/drug effects ; Oxidative Stress/drug effects ; *Acrylamides/pharmacology/chemistry ; },
abstract = {Herein, we have identified the polyfunctionalized 1-(phenylsulfonyl)-1H-indole-2-carboxylic acid derivative MTP150 for the treatment of neurodegenerative diseases owing to its efficacy in reducing protein aggregation, modulating matrix metalloproteinase activity, mitigating neuroinflammation, and enhancing DNA damage repair pathways across in vivo Caenorhabditis elegans models of Alzheimer's disease, Parkinson's disease (PD), and Huntington's disease. Further experiments in an in vivo Drosophila model of PD showed that MTP150 increased motor performance, reduced oxidative stress levels, and restored mitochondrial function in model flies. In addition, MTP150 exhibited neuroprotective effects in PD model cells, thereby supporting its therapeutic potential for this disease.},
}

Animals
*Parkinson Disease/drug therapy/genetics/metabolism
*Indoles/pharmacology/chemistry/therapeutic use
Disease Models, Animal
Caenorhabditis elegans/drug effects/genetics
Humans
*Neuroprotective Agents/pharmacology/chemistry
*Epigenesis, Genetic/drug effects
Oxidative Stress/drug effects
*Acrylamides/pharmacology/chemistry

@article {pmid41977439,
year = {2026},
author = {Bougea, A},
title = {Targeting Non-Coding RNAs as a Potential Therapeutic and Delivery Strategy Against Neurodegenerative Diseases.},
journal = {International journal of molecular sciences},
volume = {27},
number = {7},
pages = {},
doi = {10.3390/ijms27073260},
pmid = {41977439},
issn = {1422-0067},
mesh = {Humans ; *Neurodegenerative Diseases/genetics/therapy ; Animals ; *RNA, Untranslated/genetics ; MicroRNAs/genetics ; RNA, Long Noncoding/genetics ; Genetic Therapy/methods ; },
abstract = {Neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS), represent a growing global health challenge characterized by progressive neuronal loss and a lack of definitive disease-modifying treatments. This review explores the emerging potential of targeting non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and exosomal RNAs, to modulate pathogenic molecular pathways and address the underlying molecular origins of neurodegeneration. We evaluate the integration of advanced computational techniques for RNA structure prediction and gene regulatory network analysis, alongside chemical engineering strategies-such as Locked Nucleic Acids (LNAs) and phosphorothioate modifications-aimed at enhancing the stability and specificity of RNA-based molecules. Furthermore, we analyze cutting-edge delivery and editing technologies, including nanotechnology-driven solutions for precise neuronal targeting and the CRISPR/Cas13 system for direct ncRNA manipulation.The findings indicate that while challenges in delivery efficiency and long-term efficacy persist, the synergy of chemical engineering and computational modeling significantly improves the therapeutic profile of ncRNAs, with exosomal pathways offering a novel route for intercellular signaling modulation and biomarker discovery. Therapeutic interventions directed at specific clinical targets, such as miR-34a and BACE1-AS, demonstrate the capacity to influence protein aggregation and neuroinflammatory cascades. Although ncRNA-based therapies are currently in nascent stages, ongoing technological advancements in RNA editing and nanotechnology offer a transformative framework that could redefine the future of ND treatment and successfully halt disease progression rather than merely managing symptoms.},
}

Humans
*Neurodegenerative Diseases/genetics/therapy
Animals
*RNA, Untranslated/genetics
MicroRNAs/genetics
RNA, Long Noncoding/genetics
Genetic Therapy/methods

@article {pmid41977460,
year = {2026},
author = {Taboada-Jara, T and Ribalta, M and Romero-Becerra, F and Muixí, J and Bellver-Sanchis, A and Griñán-Ferré, C and Escolano, C and Pallàs, M},
title = {Usefulness of C. elegans Models of Alzheimer's and Huntington's Disease to Evaluate Novel Imidazoline I2 Receptor Ligands.},
journal = {International journal of molecular sciences},
volume = {27},
number = {7},
pages = {},
doi = {10.3390/ijms27073282},
pmid = {41977460},
issn = {1422-0067},
support = {PDC2022-133441-I00//Ministerio de Ciencia, Innovación y Universidades/ ; 2021 SGR 00357//Agència de Gestió d'Ajuts Universitaris i de Recerca/ ; PID2022-138079OB-I00//Ministerio de Ciencia, Innovación y Universidades/ ; N° 19/2015//Ministerio de Economía y Finanzas and Programa Nacional de Becas "Don Carlos Antonio López"/ ; //Càtedra UB Dr. Antoni Esteve i Subirana de Recerca en Farmacologia/ ; },
mesh = {Animals ; *Caenorhabditis elegans/metabolism/genetics ; *Huntington Disease/metabolism/drug therapy/genetics ; Disease Models, Animal ; *Imidazoline Receptors/metabolism ; Ligands ; *Alzheimer Disease/metabolism/drug therapy/genetics ; Oxidative Stress/drug effects ; Humans ; Animals, Genetically Modified ; Caenorhabditis elegans Proteins/metabolism/genetics ; Amyloid beta-Peptides/metabolism/genetics ; *Neuroprotective Agents/pharmacology ; },
abstract = {Neurodegenerative diseases such as Alzheimer's (AD) and Huntington's (HD) remain major therapeutic challenges due to limited treatment efficacy. Imidazoline I2 receptor (I2-IR) ligands have recently emerged as promising neuroprotective agents, with reported roles in modulating oxidative stress, neuroinflammation, and protein aggregation. This study evaluates the therapeutic potential of several I2-IR ligands, including Idazoxan, CR4056, and novel compounds, using Caenorhabditis elegans (C. elegans) models of AD and HD. Transgenic strains CL2006 (expressing human Aβ1-42) and EAK103 (expressing Ht513) were employed to assess locomotor activity, oxidative stress tolerance, Aβ and Ht aggregation, and sod-1 gene expression. Several ligands significantly improved movement, reduced Aβ and Ht aggregates, and enhanced antioxidant gene expression, particularly Idazoxan, LSL42, and PIP01. Notably, some compounds exhibited prooxidant effects, highlighting the utility of C. elegans for early in vivo toxicity screening. Importantly, this study provides the first in vivo evidence of the efficacy of I2-IR ligands in HD models and reinforces their potential as therapeutic candidates for HD. Overall, these findings suggest a potential role for modulation of I2-IR-related pathways in neurodegeneration and support the utility of C. elegans as a rapid, cost-effective platform for preclinical drug evaluation.},
}

Animals
*Caenorhabditis elegans/metabolism/genetics
*Huntington Disease/metabolism/drug therapy/genetics
Disease Models, Animal
*Imidazoline Receptors/metabolism
Ligands
*Alzheimer Disease/metabolism/drug therapy/genetics
Oxidative Stress/drug effects
Humans
Animals, Genetically Modified
Caenorhabditis elegans Proteins/metabolism/genetics
Amyloid beta-Peptides/metabolism/genetics
*Neuroprotective Agents/pharmacology

@article {pmid41977473,
year = {2026},
author = {Bivona, G and Ghersi, G},
title = {Microglia-Astrocyte Cooperation and Peripheral T Cells in Alzheimer's Disease: State-of-the-Art and Treatment Perspectives.},
journal = {International journal of molecular sciences},
volume = {27},
number = {7},
pages = {},
doi = {10.3390/ijms27073295},
pmid = {41977473},
issn = {1422-0067},
mesh = {*Alzheimer Disease/immunology/therapy/pathology/metabolism ; Humans ; *Microglia/metabolism/pathology/immunology ; *T-Lymphocytes/immunology/metabolism ; *Astrocytes/metabolism/pathology/immunology ; Animals ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder first described more than one century ago. Over this time, many features of the disease have been discovered and, consequently, many different approaches in the diagnosis and treatment of AD have been developed. A major assumption has guided research on AD in the past: this fatal form of cognitive decline is believed to have a pathogenic basis in the deposition of amyloid beta (Aβ) aggregates throughout the brain. Consequently, a main goal of AD therapy is to reduce Aβ load, and several monoclonal antibodies targeting amyloid are among the most recent approaches to AD treatment. However, the effectiveness of these drugs is limited, as they cannot block the progression of the disease; they only slow it down in certain conditions. Many other causative factors are known to promote the development of the disease, with immune system involvement being the most investigated. Indeed, it has been well documented that the microglial response enhances the deposition of other altered proteins, such as Tau, and induces a neurotoxic microenvironment that promotes neuronal loss. In this scenario, the interaction between microglia and astrocytes is known to accelerate pathogenic processes, and a possible role for peripheral T lymphocytes in AD pathology has also been described. An interesting hypothesis is that immune cells driving chronic inflammation might worsen AD progression and, therefore, could represent a target for treatment strategies in this disease. Thus, this review article aims to summarise the role of brain and peripheral immune molecules and cells in AD. Also, immune-based treatments for AD are described, including those targeting microglia and T cells.},
}

*Alzheimer Disease/immunology/therapy/pathology/metabolism
Humans
*Microglia/metabolism/pathology/immunology
*T-Lymphocytes/immunology/metabolism
*Astrocytes/metabolism/pathology/immunology
Animals
Amyloid beta-Peptides/metabolism

@article {pmid41980328,
year = {2026},
author = {Uti, DE and Alum, EU and Okpe, JM and Egbung, JE and Mbah, JO},
title = {Blood-brain barrier modulation for targeted central nervous system drug delivery in neurodegenerative and demyelinating disorders.},
journal = {Tissue & cell},
volume = {101},
number = {},
pages = {103524},
doi = {10.1016/j.tice.2026.103524},
pmid = {41980328},
issn = {1532-3072},
abstract = {The blood-brain barrier (BBB) plays an indispensable role in central nervous system homeostasis but it has remained a key barrier to successful treatment of neurodegenerative and demyelinating diseases. This review discusses the basis for BBB structural and functional regulation and critically discusses emerging strategies to improve therapeutic delivery in neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, and multiple sclerosis). Across pharmacological, nanotechnological, physical and genetic platforms, comes a common thread of ideas; rational and temporally-controlled BBB modulation is the uniting theme that underlies effective and safe brain-targeted therapy. Approaches such as receptor-mediated transcytosis, ligand-engineered nanocartiers, focused ultrasound with microbubbles, osmotic disruption, and electroporation or molecular or viral engineering have expanded the therapeutic landscape, but potential translational application relies upon reversibility, spatial selection, and preservation of neurovascular integrity. The discipline is shifting past proof-of-concept research to clinically-incrementally actionable paradigms anchored on pharmacokinetic accuracy, biomarker-directed goal involvement, and safety strict examination. The growing body of evidence has implied that bio-modulation of the BBB can augment the delivery of neuroprotective, anti-amyloid, anti-a-synuclein, and remyelinating therapeutic treatment with minimal systemic exposure and off-target damage. Together, BBB modulation is transitioning to become an experimental strategy of delivery, but with great clinical potential as a precision therapeutic strategy.},
}

@article {pmid41980337,
year = {2026},
author = {Pattanaik, SK and Mohanty, D and Ray, A and Jena, S and Pattanaik, S and Rath, D},
title = {Phytotherapy for ageing-related multimorbidity: Systems-level insights into Centella asiatica in diabetes and Alzheimer's Disease.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {155},
number = {},
pages = {158026},
doi = {10.1016/j.phymed.2026.158026},
pmid = {41980337},
issn = {1618-095X},
abstract = {BACKGROUND: The increasing burden of age-related illnesses underscores the urgent necessity for integrative treatment approaches that simultaneously address the complex connections between metabolic and neurodegenerative disorders. Diabetes mellitus (DM) and Alzheimer's disease (AD) are strongly interconnected through shared pathological mechanisms. Plant-based therapeutics with their rich diversity of multitarget bioactive compounds are able to compromise such a complex network. Centella asiatica (l.) Urb. (C. asiatica), A medicinal herb, it has garnered significant attention for its metabolic and neuroprotective activities in ethnopharmacology, as well as preclinical and clinical studies.

PURPOSE: In this study, we employ a computational approach to elucidate the key bioactive constituents of C. asiatica and their ability to modulate shared pathological mechanisms linking DM and AD. Provide a scientific rationale for its use as a multitarget phyto-therapeutic candidate against ageing-associated comorbidities.

METHODS: Relevant keywords were used to search databases Scopus, Science Direct, PubMed, Google Scholar and WOS. To gather the scientific evidence of its phytoconstituents, anti-diabetic activity and anti-Alzheimer's activity. Further, a network pharmacology-based approach was adopted.

RESULTS: From the identified phytoconstituents, fifty-four have favourable oral bioavailability, targeting 486 proteins. Venn interaction revealed 404 genes are cross-linked among C. asiatica, DM, and AD. Network pharmacology and enrichment analysis suggested that the PI3K-Akt signalling pathway is the key regulatory axis.

CONCLUSION: C. asiatica demonstrates potential as a multi-target phyto-therapeutic agent for managing interconnected ageing disorders, i.e., DM and AD, through modulation of the PI3K-Akt signalling pathway.},
}

@article {pmid41980560,
year = {2026},
author = {Hoffmann, D and Ahola, V and Huber, N and Natunen, T and Leskelä, S and Takalo, M and Martiskainen, H and Ballweg, S and Vorontsov, E and Selzer, S and Kallio, P and Pike, I and Sirviö, J and Haapasalo, A and Hiltunen, M},
title = {Lithium chloride alters Tau phosphorylation, kinase activity, and Rho GTPase signaling in cell models.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {198},
number = {},
pages = {119347},
doi = {10.1016/j.biopha.2026.119347},
pmid = {41980560},
issn = {1950-6007},
abstract = {Hyperphosphorylation and intracellular aggregation of Tau are pathological hallmarks of several neurodegenerative diseases, including Alzheimer's disease (AD). Clinical trials involving protein kinase inhibitors to modulate Tau phosphorylation in AD patients have shown mixed outcomes. For clinical trials using lithium salts, this could be explained by sequestration of lithium by β-amyloid and might be circumvented by selection of lithium salts with low affinity to Aβ fibrils and oligomers, promoting improved therapeutic efficacy and positive outcomes in future clinical trials. Here, we assessed the effects of lithium chloride (LiCl), a potent inhibitor of the serine/threonine kinase GSK-3β, on Tau phosphorylation and kinase activity using two cell models: the U2OS cell line overexpressing human triple mutant Tau-tGFP and a mouse cortical neuron/BV-2 co-culture model with inflammation-induced Tau hyperphosphorylation. We show that in the co-culture model, induction of inflammation led to increased Tau phosphorylation at the assessed phosphosites. LiCl reduced Tau phosphorylation depending on the concentration and the targeted phosphosites. Proteomics data from the U2OS cell line showed that LiCl treatment led to decreased phosphorylation at most of the examined phosphosites, which was consistent with the biochemical data. Our data suggest that LiCl may affect other kinases beyond GSK-3β. Additionally, we observed changes in the phosphorylation status of several proteins belonging to different Rho GTPase cycles, known to play a role in AD pathogenesis. Taken together, our data expand the understanding of the effects of LiCl on Tau phosphosites, kinases, and other AD-relevant pathways, such as Rho GTPases.},
}

@article {pmid41980692,
year = {2026},
author = {Aslam, S and Tulain, UR and Zahid, F and Ali, Z and Erum, A and Alamri, AH and Al Fatease, A and Amin, M and Wan, G and Din, FU},
title = {Brain-targeted mucoadhesive in situ gel incorporating quercetin-PEG conjugate and rivastigmine-loaded chitosan nanoparticles for Alzheimer's therapy.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {151998},
doi = {10.1016/j.ijbiomac.2026.151998},
pmid = {41980692},
issn = {1879-0003},
abstract = {Alzheimer's dementia (AD) is a progressive neurodegenerative impairment driven by a pronounced cholinergic deficit. Quercetin (QUE) and rivastigmine (RVS) have been used in the treatment of AD, however, clinical translation of QUE and RVS is limited by poor solubility, and short half-life, respectively. To overcome these limitations, QUE was PEG-conjugated (Q-PEG) and co-encapsulated with RVS in chitosan nanoparticles (CNPs) and further incorporated in mucoadhesive in situ gel for nose-to-brain delivery. Q-PEG conjugation was confirmed by Fourier transform infrared spectroscopy (FTIR) and Proton nuclear magnetic resonance ([1]HNMR). The RVS-Q-PEG-CNPsG was optimized through systematic formulation development. The optimized formulation exhibited a mean particle size (134.7 ± 0.35 nm), narrow size distribution (0.213 ± 0.01), optimal zeta potential (+21.5 ± 0.45 mV) and suitable entrapment efficiency of QUE (92.3 ± 0.50%) and RVS (81.5 ± 0.81%). Structural characterization using Transmission electron microscopy (TEM), FTIR, X-Ray diffraction (XRD), and Differential scanning calorimetry (DSC) confirmed spherical morphology, components compatibility, amorphous nature and thermal stability, respectively. Moreover, the poloxamer based in situ gel demonstrated homogeneity, optimal viscosity and robust mucoadhesive strength, thereby markedly enhancing drug retention of CNPs at the administration site. Moreover, it depicted a sustained drug release profile in vitro, and enhanced nasal permeation, ex vivo. Additionally, histopathological evaluation validated the safety and mucosal compatibility of the formulation. Furthermore, pharmacokinetic studies demonstrated significantly enhanced brain bioavailability of RVS-Q-PEG-CNPsG (5.6 ~ fold and 12.6 ~ fold) compared to intranasal free RVS and QUE. These findings suggested that intranasally administered RVS-Q-PEG-CNPsG provides effective brain delivery, which may be a promising approach for the treatment of AD.},
}

@article {pmid41981183,
year = {2026},
author = {Belhaj, I and Åmellem, I and Tartanoglu, CH and Weidemann, HM and Vallenari, EM and Yang, M and Chaudhry, FA and Bjørås, M and Storm-Mathisen, J and Bergersen, LH},
title = {Lactate treatment improves brain biochemistry and cognitive function in transgenic Alzheimer's and wild-type mice.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-48154-6},
pmid = {41981183},
issn = {2045-2322},
}

@article {pmid41966729,
year = {2026},
author = {Stinson, SE and Shadrin, AA and Rahman, Z and Rødevand, L and Broce, IJ and Selbæk, G and Stefansson, H and Haavik, J and Parker, N and Koch, E and Frei, O and O'Connell, KS and Smeland, OB and Djurovic, S and Dale, AM and van der Meer, D and Andreassen, OA},
title = {Distinct metabolic signatures of Alzheimer's and Parkinson's disease revealed through genetic overlap.},
journal = {EBioMedicine},
volume = {127},
number = {},
pages = {106254},
doi = {10.1016/j.ebiom.2026.106254},
pmid = {41966729},
issn = {2352-3964},
abstract = {BACKGROUND: Metabolic dysfunction is a major risk factor for neurodegeneration, yet the genetic architecture linking systemic metabolism to Alzheimer's disease (AD) and Parkinson's disease (PD) remains unclear.

METHODS: We integrated genome-wide association data for 249 circulating metabolites and proglucagon with summary statistics for AD, PD, and cardiometabolic traits. Genetic correlations, polygenic overlap, causal relationships, and shared genetic loci were quantified using linkage disequilibrium score regression, high-definition likelihood, bivariate mixture modelling, Mendelian randomisation, and conjunctional false discovery rate analyses, followed by functional and tissue-specific enrichment analyses.

FINDINGS: AD displayed a metabolic-genetic profile aligned with body mass index, type 2 diabetes, coronary artery disease, and stroke, whereas PD exhibited largely opposing patterns (Spearman's rs = -0.26). Mendelian randomization analyses supported causal effects of lipoprotein subclasses, glutamine, and proglucagon on AD risk, with opposite or null effects in PD. Shared loci between metabolites and AD were enriched for lipid metabolism and cholesterol transport, whereas PD-associated loci were enriched for mitochondrial function, vesicle trafficking, and stress-response signalling.

INTERPRETATION: AD and PD are shaped by fundamentally distinct metabolic-genetic architectures. Metabolically targeted interventions, particularly those modulating lipid, amino acid, and proglucagon pathways, may require disease-specific and genetically informed strategies for prevention and treatment of neurodegenerative diseases.

FUNDING: Novo Nordisk Foundation (NNF23OC0099658), Marie Skłodowska-Curie Actions (801133), the Research Council of Norway (334920, 351751, 296030, 324252, 324499, 326813), the National Institutes of Health (U24DA041123, R01AG076838, U24DA055330, OT2HL161847, 5R01MH124839-02), NordForsk (164218), South-Eastern Norway Regional Health Authority (2020060), and the European Union's Horizon 2020 (847776, 964874, 101057454).},
}

@article {pmid41966804,
year = {2026},
author = {Tejero, A and Benito-Patón, V and Griñán-Ferré, C and Pallás, M and León-Navarro, D and Martín, M},
title = {Resveratrol induces molecular changes in cholesterol homeostasis in SAMP8 mice cerebellum.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {198},
number = {},
pages = {119319},
doi = {10.1016/j.biopha.2026.119319},
pmid = {41966804},
issn = {1950-6007},
abstract = {Resveratrol (Rsv) is a natural polyphenol with neuroprotective properties that modulates several pathways implicated in Alzheimer's disease (AD). Cholesterol homeostasis is disrupted in AD patients, and this imbalance plays a key role in amyloid precursor protein (APP) processing, β-amyloid aggregation and membrane stability. The effect of Rsv on the cerebellum, an emerging structure in cognitive networks and AD pathology due to its high connectivity with other brain regions, remains largely unexplored. This study aims to characterize the effects of Rsv on the cerebellum of SAMP8 mice, an animal model of AD, at different ages (5- and 7-month-old mice) and to investigate how it act as a neuroprotective polyphenol in this structure via modulation of cholesterol metabolism. Aging caused a significant increase in cerebellar membrane free cholesterol levels, which were reversed by Rsv treatment. HMG-CoA reductase levels were significantly reduced by Rsv treatment in 5-month-old mice, suggesting that this polyphenol modulates cholesterol synthesis. Parameters related to cholesterol trafficking were also modulated, with increased LDL receptor levels, but without affecting ApoE. Mitochondrial electron transport chain complexes were also upregulated by Rsv treatment in 5-month-old animals, without affecting mitochondrial dynamics. Collectively, these data demonstrate-for the first time-that Rsv modulates key aspects of cholesterol metabolism and mitochondrial function in the cerebella of SAMP8 mice.},
}

@article {pmid41968216,
year = {2026},
author = {Zhu, S and Li, Y and Lin, C and Liu, X and Luo, Y and Qian, H and Tang, Z},
title = {Combined with network pharmacology, the therapeutic effect and mechanism of coumarins from Chimonanthus praecox extract in the treatment of Alzheimer's disease were investigated.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {41968216},
issn = {1432-1912},
support = {grant number 82360873//National Natural Science Foundation General Project/ ; No: Qiankeheji-ZK [2022]- General 471//Guizhou Provincial Department of Science and Technology Project/ ; Contract No.: YCXKYB2023017//Construction Task of Graduate Education Innovation Plan Project of Guizhou University of Traditional Chinese Medicine/ ; },
abstract = {The objective of this study is to investigate the therapeutic potential and underlying mechanisms of Chimonanthus praecox-derived coumarins in Alzheimer's disease (AD)-related neuroinflammatory and cognitive impairments. Network pharmacology was employed to identify active components and targets of Chimonanthus praecox-derived coumarins, followed by intersection analysis with AD-related genes. A protein-protein interaction (PPI) network was constructed and subjected to functional enrichment analysis. Molecular docking was performed to validate the binding affinity between key compounds and core targets. An AD-like rat model characterized by aging-related cognitive impairment and neuroinflammation was established using D-galactose and aluminum chloride, and therapeutic effects of coumarin treatment were evaluated via behavioral testing, HE staining, immunohistochemistry, Western blotting, and electroencephalography (EEG). Four active compounds, 58 drug targets, and 19 AD-related intersecting targets were identified, primarily enriched in neuroinflammation-related pathways including NF-κB p65, NLRP3, and Alzheimer's disease-related pathways. Molecular docking showed strong binding of key coumarin derivatives to amyloid precursor protein (APP), apolipoprotein E4 (APOE4), NF-κB p65, and prostaglandin-endoperoxide synthase 2 (PTGS2). In vivo, Chimonanthus praecox-derived coumarin treatment improved aging-associated cognitive deficits, alleviated hippocampal neuronal injury, inhibited APP and APOE4 expression, and significantly downregulated NF-κB p65, PTGS2, IL-6, and NLRP3 levels. EEG analysis further confirmed attenuation of abnormal neural activity. Chimonanthus praecox-derived coumarins exert neuroprotective and anti-inflammatory effects through multi-target modulation, supporting their potential as candidate agents for AD-related neuroinflammatory and cognitive dysfunction.},
}

@article {pmid41968555,
year = {2026},
author = {Kaur, K and Goel, H and Chawla, PA and Chawla, V},
title = {Trends and Perspectives in the Targeting of Brain Through Ethosomal Formulations.},
journal = {Recent advances in drug delivery and formulation},
volume = {},
number = {},
pages = {},
doi = {10.2174/0126673878418338251203100909},
pmid = {41968555},
issn = {2667-3886},
abstract = {Neurological diseases such as Alzheimer's disease, Schizophrenia, anxiety, Parkinson's disease, and migraine are serious conditions that continue to threaten mankind. The cases of brainrelated disorders are increasing worldwide and are closely related to physiological, genetic, and environmental factors. Direct drug delivery to the brain is crucial for the effective treatment and prevention of these conditions. However, due to the presence of a lipophilic barrier, i.e., the bloodbrain barrier, the entry of therapeutic agents into the brain is restricted, resulting in a lower concentration at the targeted site. As a solution to this problem, the direct nose-to-brain connection is attracting attention for its effective, precise, non-invasive delivery of drugs via the olfactory and trigeminal pathways. However, there are some limitations, like permeability across the nasal mucosa and mucociliary clearance. Therefore, to overcome these restrictions, the use of nanocarriers, particularly ethosomes, is being attempted. This review paper delves into recent research papers and reports on ethosomes developed for intranasal delivery towards the management of neurological conditions. Ethosomes demonstrated an exceptional capacity to facilitate drug accumulation at targeted sites, owing to their ability to bypass first-pass metabolism, their flexible nature, and the presence of penetration enhancers. The high ethanol content in the composition significantly increases the fluidity of the lipid bilayer, allowing for better interaction of this vesicular system with the blood-brain barrier. Furthermore, the functionalization of ethosomes can enhance the specific delivery of drugs, increase patient compliance, and minimize side effects. However, no intranasal ethosomes for direct brain delivery have progressed from preclinical testing to the bedside of patients. They are still in the experimental phase, particularly in animals or in vivo lab models. The possibilities of toxic effects, the use of high amounts of ethanol, and irregular nasal absorption are a few concerns that need to be addressed. The increasing demand for intranasal delivery suggests that ethosomes may play a pivotal role in the management and treatment of brain-related conditions, but this will only occur after a substantial number of clinical trials confirm their safety and efficacy for human consumption. This review explores such possibilities and highlights current trends and future perspectives in targeting the brain with ethosomal formulations.},
}

@article {pmid41969035,
year = {2026},
author = {Shum, CK and Shea, YF and Au Yeung, TW and Chan, CCY and Chan, WC and Cheng, WK and Cheung, NYF and Cho, DHY and Chow, TK and Fong, GCY and Ip, BYM and Kwok, JSH and Lai, BMH and Lam, LCW and Lee, ATC and Lok, CM and Mok, KY and Ng, DKK and Siu, DYW and Yeung, PY and Tam, SKF},
title = {Consensus statement on the use of Alzheimer's disease biomarkers and anti-amyloid therapies in Hong Kong.},
journal = {Hong Kong medical journal = Xianggang yi xue za zhi},
volume = {},
number = {},
pages = {},
doi = {10.12809/hkmj2514198},
pmid = {41969035},
issn = {1024-2708},
abstract = {Alzheimer's disease (AD) is the most common aetiology of cognitive impairment worldwide and in Hong Kong. There have been rapid advances in the use of biomarkers for the diagnosis of AD and in the availability of anti-amyloid therapies (AAT) to slow cognitive and functional decline. At present, there is no consensus in Hong Kong regarding the application of AD biomarkers or the use of AAT. A multidisciplinary group of 20 medical specialists from five professional societies discussed issues related to the application of biomarkers for the diagnosis of AD pathology and the use of AAT, and reviewed the evidence in the context of local experience to inform recommendations. A modified Delphi approach was adopted to finalise the recommendations. Consensus was defined as ≥75% agreement on a 9-point Likert scale among panellists. The panel finalised 26 consensus statements addressing the use of AD biomarkers, including neuroimaging and fluid biomarkers, as well as the use of AAT, including inclusion criteria, serial neuroimaging monitoring during treatment, and management of infusion reactions. These recommendations are relevant to the Hong Kong healthcare setting and may serve as guidance for doctors across specialties to facilitate appropriate management of AD.},
}

@article {pmid41969962,
year = {2026},
author = {İlhan, N and Keskin, E and Şahin, E and Alaylıoğlu, M and Samancı, B and Çamoğlu, T and Yurttaş, Z and Sordu, P and Ildız, S and Ayaz, G and Yediel, BŞ and Azzouz, SS and Bilgiç, B and Hanağası, HA and Gürvit, İH and Ak, DG and Dursun, E},
title = {The mRNA Expression Levels of General Transcription Factors Altered in Alzheimer Cases Possibly Due to Amyloid Beta 1-42 Exposure.},
journal = {Noro psikiyatri arsivi},
volume = {63},
number = {},
pages = {341-349},
pmid = {41969962},
issn = {1300-0667},
abstract = {INTRODUCTION: Given the global gene expression alterations associated with amyloid beta (Aβ), a hallmark of Alzheimer's disease (AD) pathology, this study aimed to investigate its potential role in modulating gene expression through the regulation of specific transcription factors (TFs).

METHODS: Using a combination of protein-protein interaction prediction tools and transcriptional regulatory interaction databases, we identified JUN, FOS, ATF2, ATF4, RELA, NF-κB, SMAD3, STAT1, STAT3, and SP1 as potential candidate TFs that might be involved in Aβ1-42 related pathways. We then conducted in vitro studies to demonstrate a direct effect of Aβ on these TFs and a case-control study to investigate any alterations of selected TFs in human samples. In vitro studies included HEK293 T cells treated with 0.09 µM and 10 µM Aβ1-42. The expression levels of the TFs were assessed by qRT-PCR. The mRNA expression levels of selected target transcription factors that have the highest PPI scores, namely JUN, FOS, and RELA, were also investigated in blood samples from core Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarker-confirmed AD cases and plasma ALZpath pTau217-confirmed healthy subjects.

RESULTS: In vitro studies indicated that the mRNA expression of most of the TFs was altered due to either the dose of Aβ or the period of treatments. JUN, FOS, NFKB, and SP1 mRNA expression were increased, while STAT1 and ATF2 were decreased within 24 hours of at least one dose of Aβ treatment. At 48 hours of treatment, FOS, STAT1, STAT3, ATF2, and SP1 were higher, whereas RELA, SMAD3, and NFKB were lower in Aβ-treated groups. At 72h of treatments, the ATF4 and NFKB expressions were high, whereas JUN FOS, RELA, STAT1, STAT3, ATF2, and SP1 were low in Aβ treated groups. Human samples showed that the mRNA levels of JUN and RELA were significantly higher in blood samples from AD cases compared to those from healthy individuals.

CONCLUSION: Alterations in the expression levels of TFs in response to Aβ exposure may explain the alterations of the expression levels of genes that these TFs regulate. Given that, understanding the transcriptional effects of Aβ and its regulatory role on TFs may provide a perspective for the physiological roles of Aβ and the molecular pathways underlying AD pathogenesis.},
}

@article {pmid41970152,
year = {2026},
author = {Lourdel, C and Launay, A and Couteau, A and Bomia, D and Pointereau, S and Bulteau, S and Tessier, F and Thevenet, S and Ahoure, C and Belloeil, V and Robert, G and Taudin, N and Manivel, L and Daucé-Fleuret, L and Richomme, C and Camus, V and Brit, S and Léger, J and Desmidt, T},
title = {The I-Learn Cognition and Behavior program for non-pharmacological treatment of agitation in nursing home residents with neurocognitive disorders: A cluster randomized trial.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {2},
pages = {e70232},
pmid = {41970152},
issn = {2352-8737},
abstract = {INTRODUCTION: The "I-Learn Cognition and Behavior" program, integrating e-learning and simulation, aims to equip long-term care facility staff with non-pharmacological approaches for managing agitation in residents with neurocognitive disorders. This study evaluated the program's effectiveness.

METHOD: In this multicenter cluster-randomized trial, long-term care facilities served as the randomization units for a population of residents with neurocognitive disorders and agitation who underwent blinded assessments at baseline, 3, 6, and 10 months. Assessments included the Cohen-Mansfield Agitation Inventory (CMAI) as the primary outcome, the Neuropsychiatric Inventory-Nursing Home (NPI-NH), the Quality of Life in Alzheimer's Disease questionnaire, the Maslach Burnout Inventory (MBI), psychotropic use, and hospitalizations. Mixed-effects models analyzed changes in outcomes.

RESULTS: Twelve long-term care facilities were randomized to receive the I-Learn program (intervention) or usual care (control). One hundred sixty-nine residents were enrolled. There were no significant differences in total CMAI score changes between groups. The intervention group demonstrated significant reduced CMAI non-aggressive verbal agitation, MBI depersonalization, and psychotropic medication use (higher withdrawal rates and lower dosage increases) compared to the control group. NPI-NH scores decreased less in the intervention group.

DISCUSSION: The I-Learn program demonstrated potential for improving specific aspects of agitation in residents and well-being in caregivers while significantly reducing psychotropic medication use. "I-Learn Cognition and Behavior" is an easily accessible program with the potential for widespread distribution, contributing to improved well-being and quality of care in long-term care facilities for managing agitation in residents with neurocognitive disorders.},
}

@article {pmid41970809,
year = {2026},
author = {Kherachi, R and Daoud, I and Melkem, N and Chelihi, A and Al-Shuhaib, MBS and Hamouda, S and Meawad, SB and El-Arabey, AA and Abdalla, M},
title = {In silico investigation of 4-(Trifluoromethyl)benzohydrazide derivatives as potential anti-Alzheimer's agents by targeting acetylcholinesterase and butyrylcholinesterase.},
journal = {In silico pharmacology},
volume = {14},
number = {1},
pages = {111},
pmid = {41970809},
issn = {2193-9616},
abstract = {UNLABELLED: Alzheimer's disease (AD) is a condition that mostly affects individuals in the latter stages of life. Due to the importance of inhibiting acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in improving cholinergic transmission in the brain, both enzymes were targeted to provide a direct therapeutic approach against AD. In this study, we examined a novel set of derivatives of 4-(Trifluoromethyl)benzohydrazide, which have been identified for their potential to prevent the progression of the aforementioned illness. In this study, various computational techniques, including molecular docking, molecular dynamics (MD) simulations, bioisosteric replacement, and ADMET predictions, were utilized to discover potential inhibitors of AChE and BuChE from a set of twenty-five compound derivatives. The most promising inhibitors for each target, namely 2 s for AChE (- 7.674 kcal/mol) and 2r for BuChE (- 6.144 kcal/mol), along with their isosteres, were identified based on their high docking scores. Furthermore, the stability of these inhibitors was confirmed through MD simulation, and they exhibited favorable drug-likeness properties and safety profiles. Hence, it is essential to do more research to advance their potential as pharmaceutical agents for the treatment of AD.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-026-00605-8.},
}

@article {pmid41971324,
year = {2026},
author = {Wang, B and Deng, F and Liu, Z and Tian, J and Li, Y and Mao, Y and Song, H},
title = {Clinical application of fecal microbiota transplantation and its influencing factors.},
journal = {Frontiers in microbiology},
volume = {17},
number = {},
pages = {1807071},
pmid = {41971324},
issn = {1664-302X},
abstract = {Fecal microbiota transplantation (FMT) is an emerging therapy that has received significant attention in recent years, although its origins can be traced back to 4th-century China. In modern medicine, FMT has been incorporated into clinical guidelines for the treatment of recurrent Clostridioides difficile infection. By re-establishing a healthy gut microbiota and regulating the immune system, FMT has potential therapeutic effects on various diseases, such as gastrointestinal diseases, diabetes, tumors, Alzheimer's disease, and liver disease. However, its efficacy varies based on the type of disease and individual differences. The clinical application of FMT is influenced by multiple factors, including fecal matter processing, administration route, dosage, donor screening, and recipient detection. Currently, FMT faces numerous challenges, including the need to verify the stability and durability of its efficacy, standardize donor screening criteria, and optimize fecal processing and administration. Future research is expected to reveal the mechanisms of action of FMT, optimize treatment protocols, and refine its safety, efficacy, and convenience, thereby bringing hope for patients with complex and challenging diseases.},
}

@article {pmid41971579,
year = {2026},
author = {Gu, S and Yin, W and Xie, M and He, C and Bian, Y and Li, L and Lu, W and Wang, Q},
title = {Isoquinoline alkaloids in Coptis chinensis to treat Alzheimer's disease through promoting growth of Bifidobacterium breve inhibiting abnormal autophagy using a novel AI high-content intelligent imaging system.},
journal = {Chinese herbal medicines},
volume = {18},
number = {2},
pages = {405-419},
pmid = {41971579},
issn = {2589-3610},
abstract = {OBJECTIVE: Coptis chinensis has been shown to increase beneficial intestinal bacteria and treat Alzheimer's disease (AD). Bifidobacterium breve can effectively treat AD through the gut-brain axis. Therefore, this study aimed to study the joint effects of C. chinensis and B. breve in the treatment of AD.

METHODS: 16S rRNA was used to test the abundance of bacterial flora in APPswe/PS1ΔE9 mice after C. chinensis administration. To determine the efficacy of C. chinensis combined with B. breve on AD, pathological section staining, Barnes maze, Western blotting and ELISA were utilized to confirm the improvement of cognitive dysfunction in AD mice after administration. In order to elucidate the pharmacodynamic components of monomers in C. chinensis, network pharmacology was used to screen the components related to autophagy and confirm the pharmacodynamic effects by artificial intelligence (AI) high-content intelligent imaging.

RESULTS: The results of 16S rRNA sequencing indicated that C. chinensis could modulate the abundance of B. breve in AD mice. Pathological assessments, Barnes maze testing, and additional experiments have shown that C. chinensis combined with B. breve can improve the memory and learning ability of AD mice by reducing neuronal apoptosis and amyloid-β (Aβ) peptide deposition. Network pharmacology combined with AI high-content intelligent imaging technology and Western blotting experiments demonstrated that magnoflorine, 13-methylberberine and palmatrubine in C. chinensis could exert neuroprotective effects in AD mice by up-regulating p62 protein expression while down-regulating Beclin-1 and microtubule-associated protein 1 light chain 3 II (LC3II) protein levels, thereby modulating autophagy-related pathways.

CONCLUSION: C. chinensis can enhance the abundance of beneficial bacteria in the gut and ameliorate cognitive dysfunction in AD mice by interacting with B. breve. Moreover, magnoflorine, 13-methylberberine, and palmatrubine within C. chinensis can also mitigate excessive autophagy and oxidative stress in nerve cells.},
}

@article {pmid41972397,
year = {2026},
author = {Schurman, CA and Kaur, G and Kaya, S and Bons, J and Aguirre, CG and Liu, Q and King, CD and Wilson, KA and Baker, HL and Hady, M and Luna, NM and Bieri, G and Villeda, SA and Ellerby, LM and Schilling, B and Alliston, T},
title = {Alzheimer's Disease Risk Factor APOE4 Exerts Dimorphic Effects on Female Bone.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e23511},
doi = {10.1002/advs.202523511},
pmid = {41972397},
issn = {2198-3844},
support = {/NH/NIH HHS/United States ; P30AR075055/AR/NIAMS NIH HHS/United States ; R01DE019284-14S1-Alzheimer's/DE/NIDCR NIH HHS/United States ; Disease Supplement: R01DE01928-11A1/DE/NIDCR NIH HHS/United States ; R01AG067740/AG/NIA NIH HHS/United States ; R01AG077770/AG/NIA NIH HHS/United States ; P01AG066591/AG/NIA NIH HHS/United States ; S10OD028654/AG/NIA NIH HHS/United States ; T32AG000266/AG/NIA NIH HHS/United States ; },
abstract = {Individuals with Alzheimer's disease (AD) are at an increased risk of bone fracture, while osteoporosis in women is one of the earliest predictors of AD. Yet the mechanisms linking cognitive decline and skeletal deterioration remain poorly defined. Proteomic analysis of cortical bone from aged 21-month-old mice revealed strong enrichment of neurodegeneration-associated proteins, including apolipoprotein E (Apoe) and amyloid precursor protein. Apoe localized specifically to osteocytes, with expression in aged female bone nearly twice that of young 4-month-old male bone. Because human APOE alleles confer different age-related AD risks, we examined their roles in bone using humanized APOE2, APOE3, and APOE4 knock-in mice and analyzed bone and hippocampus from the same animals. APOE4 produced marked sex-specific effects on the bone transcriptome and proteome compared with APOE2 or APOE3. Strikingly, APOE4-associated proteomic disruptions were stronger in female bone than in the hippocampus. Functionally, APOE4 caused bone fragility in females without altering cortical structure. These deficits stemmed from impaired osteocyte perilacunocanalicular remodeling. Our findings identify APOE4 as a molecular driver of early osteocyte dysfunction and reduced bone quality, disproportionately affecting females. These findings highlight osteocytes as potential targets for early diagnosis of age-related cognitive impairment and treatment for bone fragility, in females.},
}

@article {pmid41972598,
year = {2026},
author = {Travers-Lesage, V and Since, M and Wang, A and Davis, A and Fayolle, D and Bernay, B and Modeste, F and Nachon, F and Brazzalotto, X and Crouzier, L and Sopkova-De Oliveira Santos, J and Maurice, T and Dallemagne, P and Rochais, C},
title = {Rational Design and Evaluation of Rivastigmine-Based Pleiotropic Prodrugs for the Treatment of Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00170},
pmid = {41972598},
issn = {1948-7193},
abstract = {The multifactorial origin of Alzheimer's disease (AD) is currently being addressed with the development of combination therapy or multitarget directed ligands. If the conventional approach of targeting acetylcholinesterase (AChE) for AD treatment has limitations, it could offer opportunities for a polypharmacological approach by designing covalent pseudoirreversible prodrugs inspired by rivastigmine's mechanism of action. This study focuses on introducing aminated drugs to the rivastigmine carbamate moiety, namely, fluoxetine and memantine, which have shown synergy with cholinesterase inhibition. These innovative carbamates target sustained drug release through covalent pseudoirreversible cholinesterase inhibition, strategically balancing inhibitory potency, selectivity, mechanism, and reactivation kinetics. This comprehensive approach demonstrates the potential of targeting ChE via a covalent mechanism and provides valuable insights into the structure-activity relationships of these derivatives. Interestingly, this study provides a useful biochemical toolbox for characterizing pseudoirreversible cholinesterase carbamate-type inhibitors. The most promising compound was evaluated in in cellulo and in vivo AD models, highlighting the potential of polypharmacological interventions as innovative and multifaceted anti-AD drugs.},
}

@article {pmid41972916,
year = {2026},
author = {Li, Y and Wang, G and Xiong, C and Shan, G and Cao, Y and Llibre-Guerra, J and Hassenstab, J and McDade, E and Bateman, RJ},
title = {Statistical models for Alzheimer's disease clinical trials: Lessons learned from the DIAN-TU Platform Trial.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261441645},
doi = {10.1177/13872877261441645},
pmid = {41972916},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) clinical trials often involve uneven follow-up durations and long-term open-label extensions (OLE), yet conventional statistical models are typically designed for fixed schedules, limiting their efficiency in such settings.ObjectiveTo describe and illustrate alternative statistical modeling approaches developed and implemented in the Dominantly Inherited Alzheimer Network Trials Unit platform trial to optimally leverage data with irregular and extended follow-up.MethodsWe present three complementary models: (1) a Cox proportional hazards model for recurrent disease progression events that uses all observed worsening events rather than only the first event; (2) a parametric disease progression model based on estimated years from expected symptom onset that estimates proportional slowing or time delay in disease progression; and (3) piecewise linear mixed-effects models tailored to the "gap" period between the double-blind phase and OLE, accommodating variable off-treatment intervals and missing interim data. All methods are illustrated with hypothetical examples, and ready-to-use SAS code is provided in the Supplemental Material.ResultsThe proposed models successfully handle complex longitudinal data structures typical trials with OLE phases, offering greater statistical efficiency and more comprehensive capture of treatment effects over extended periods compared with traditional approaches.ConclusionsThese flexible, efficient statistical models are well-suited for rare disease and long-duration AD trials. Wider adoption and further validation of these approaches may enhance the power and interpretability of future neurodegenerative disease trials.},
}

@article {pmid41972921,
year = {2026},
author = {Harrington, EE and Bock, JE},
title = {Honor culture and cognitive aging: Honor endorsement and deficits in memory aging and Alzheimer's disease knowledge.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261441602},
doi = {10.1177/13872877261441602},
pmid = {41972921},
issn = {1875-8908},
abstract = {BackgroundIdentifying deficits in the public's memory aging knowledge is a promising avenue for improving our understanding of Alzheimer's disease (AD) risk and developing effective education and intervention strategies. Yet, it is important to contextualize knowledge within culturally relevant frameworks that may not only contribute to the extent of individuals' knowledge, but also to the reception of developed educational and intervention programs.ObjectiveOne prominent culture within the United States (U.S.) that has largely been neglected within AD research is the culture of honor, or those that prioritize the defense and maintenance of reputation.MethodsUsing an online sample, the present study examined 998 U.S. adults' endorsement of honor culture norms and knowledge of normal and pathological memory aging knowledge, as well as AD specific knowledge. Hierarchical linear regression analyses (controlling for age, sex, race/ethnicity, educational attainment, and dementia experience) examined associations between honor endorsement and each type of memory aging knowledge.ResultsGreater honor endorsement was associated with worse knowledge of normal memory aging, pathological memory aging, and AD. Exploratory analyses that examined links to domains of AD knowledge revealed that greater honor endorsement was specifically linked with worse knowledge related to AD risk factors, symptoms, treatment and management, life impact, and caregiving.ConclusionsThe present research advances our understanding of deficits in the public's memory aging knowledge within the context of U.S. honor cultures and highlights a need for the developmental of culturally relevant education and intervention efforts.},
}

@article {pmid41962336,
year = {2026},
author = {Kumar, A and Khan, MN and Tiwari, AK and Islam, MM and Judder, MI},
title = {Targeting GPX4 in neurodegenerative disorder: Unlocking ferroptosis as a therapeutic frontier.},
journal = {Tissue & cell},
volume = {101},
number = {},
pages = {103523},
doi = {10.1016/j.tice.2026.103523},
pmid = {41962336},
issn = {1532-3072},
abstract = {Ferroptosis is a regulated form of cell death characterized by iron-dependent lipid peroxidation and disruption of cellular redox homeostasis. Among the key regulators of this process, glutathione peroxidase 4 (GPX4) plays a central role in maintaining membrane lipid integrity by reducing phospholipid hydroperoxides using glutathione as a cofactor. Impairment of GPX4 activity leads to the accumulation of toxic lipid peroxides, ultimately triggering ferroptotic cell death. Increasing evidence suggests that dysregulation of GPX4-mediated antioxidant defense contributes to the pathogenesis of several neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions characterized by oxidative stress and iron imbalance. In recent years, targeting GPX4 and its associated metabolic pathways has emerged as a promising therapeutic strategy for modulating ferroptosis. This review summarizes the molecular mechanisms governing GPX4 regulation, including its interaction with glutathione metabolism, lipid peroxidation pathways, and iron homeostasis. Furthermore, we discuss emerging pharmacological modulators of GPX4 and ferroptosis, highlighting their potential applications in the treatment of neurological diseases. Understanding the regulatory network surrounding GPX4 may provide new insights into ferroptosis-based therapeutic interventions and facilitate the development of targeted strategies for the management of neurodegenerative disorders.},
}

@article {pmid41962454,
year = {2026},
author = {Fin, S and Moayedikia, A and Wiil, UK},
title = {Dual-model deep learning for Alzheimer's prognostication.},
journal = {Computers in biology and medicine},
volume = {208},
number = {},
pages = {111672},
doi = {10.1016/j.compbiomed.2026.111672},
pmid = {41962454},
issn = {1879-0534},
abstract = {Disease-modifying therapies for Alzheimer's disease demand precise timing decisions, yet current predictive models require longitudinal clinical observations and provide no uncertainty quantification-rendering them impractical at the critical first-visit encounter when treatment decisions must be made. We developed PROGRESS (PRognostic Generalization from REsting Static Signatures), a dual-model deep learning framework that transforms a single baseline cerebrospinal fluid (CSF) biomarker assessment into actionable prognostic estimates without requiring prior clinical history. The framework addresses two complementary clinical questions: a probabilistic trajectory network predicts individualized cognitive decline parameters with calibrated uncertainty bounds that achieve near-nominal coverage, enabling honest prognostic communication rather than false precision; and a deep survival model estimates time-to-conversion from mild cognitive impairment to dementia. Using data from over 3000 participants across 43 Alzheimer's Disease Research Centers in the National Alzheimer's Coordinating Center database, PROGRESS substantially outperforms existing approaches including Cox proportional hazards, Random Survival Forests, and gradient boosting methods for survival prediction. Risk stratification identifies patient groups with seven-fold differences in conversion rates, enabling clinically meaningful treatment prioritization. Leave-one-center-out validation demonstrates robust generalizability, with survival discrimination remaining strong across all held-out clinical sites despite heterogeneous measurement conditions spanning four decades of assay technologies. By combining superior survival prediction with trustworthy trajectory uncertainty quantification, PROGRESS bridges the gap between biomarker measurement and personalized clinical decision-making-providing the prognostic timeline that current staging approaches cannot offer.},
}

@article {pmid41964075,
year = {2026},
author = {Andreozzi, E and Yagi, T and Wildsmith, K and Rawal, S and Horie, K and Boyd, P and Takahashi, E and Barthélemy, NR and Aluri, J and Charil, A and Reilhac, A and Gordon, BA and Flores, S and Verbel, D and Sauter, N and Benzinger, TLS and McDade, E and Mummery, C and , and , and Zhou, J and Bateman, RJ and Reyderman, L},
title = {Etalanetug (E2814) in dominantly inherited Alzheimer's disease: an open-label phase 1b/2 study to assess safety and target engagement in participants with mild to moderate cognitive impairment.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02047-y},
pmid = {41964075},
issn = {1758-9193},
abstract = {INTRODUCTION: Etalanetug (E2814) is designed to delay the clinical progression of Alzheimer's disease (AD) by binding to the microtubule binding region (MTBR) of tau implicated in seeding and spreading of tau pathology. Dominantly inherited Alzheimer's disease (DIAD) is a rare form of the disease (< 1%), having similar changes in the tau distribution and pathology to sporadic AD. Herein, we report the safety, pharmacology and biomarker results of the etalanetug Study 103 in DIAD patients.

METHODS: Study 103 enrolled participants with mild-to-moderate cognitive impairment due to DIAD who received etalanetug intravenously every 4 weeks escalating from 750 mg, 1500 mg, 3000 mg, to 4500 mg. After ascending to 4500 mg, patients received 4500 mg for up to 108 weeks. Tau pathology biomarkers, ptau217 and MTBR-tau243 were measured in CSF. Additional assessments included tau PET ([[18]F]MK-6240) and MRI. Pharmacodynamic effects of etalanetug on biomarkers were evaluated. Untreated participants from the DIAN Observational and DIAN-TU studies trial served as natural history controls.

RESULTS: Overall, 8 participants enrolled in Study 103. Etalanetug reduced concentrations of ptau217 30.4% after 12 weeks (n = 7), 48.6% at 36 weeks (n = 5), and 57.9% at 108 weeks (n = 2). Etalanetug treatment reduced concentrations of MTBR-tau243 by 50.6% in DIAD participants (n = 7) after 12 weeks of treatment. Maximal reduction in MTBR-tau243 levels (71.6%) was observed at week 36 (n = 4) and was sustained to 108 weeks (n = 2). In healthy volunteers who lack tau pathology, etalanetug had no effect on MTBR-tau243 or ptau217 after 12 weeks of treatment. Three DIAD patients had tau PET acquired at week 60 and week 108. The data indicate that the tau PET SUVr signal remains stable overall, with a trend towards decrease over time. At 108 weeks, no tau accumulation was observed via tau PET in any of the 3 patients. Three participants experienced treatment-related adverse events (AEs) with the 3000 mg dose; additionally, 5 serious AEs total were reported in 3 participants.

DISCUSSION: Etalanetug treatment in these symptomatic participants with DIAD was tolerated across dose levels, and immunogenicity was found to be minimal. Etalanetug demonstrated effects on both hyperphosphorylated tau and tau tangle pathology. Taken together, the data support continued evaluation of etalanetug as an AD disease-modifying therapy.

TRIAL REGISTRATION: NCT04971733 (registration date: 2021-07-20).},
}

@article {pmid41964934,
year = {2026},
author = {Ghosh, N and Pathak, S and Bera, R and Sharma, A and Kakkar, D and Kurmi, BD and Srivasatava, P and Ghosh, M and Karwasra, R and Ansori, ANM and Das, S and Sharma, N},
title = {Biomimetic nanocarriers as advanced drug delivery strategies in neurological disorders.},
journal = {Expert opinion on drug delivery},
volume = {},
number = {},
pages = {},
doi = {10.1080/17425247.2026.2659924},
pmid = {41964934},
issn = {1744-7593},
abstract = {INTRODUCTION: Neurological disorders represent a major and growing global health challenge due to complex central nervous system pathology and limited drug penetration across the blood - brain barrier. Conventional therapies are largely symptomatic and often fail to achieve sufficient brain bioavailability or disease modification. Biomimetic nanocarriers have emerged as a promising strategy to improve brain targeting and therapeutic efficacy.

AREAS COVERED: This review discusses recent advances in biomimetic nanocarriers for the treatment and diagnosis of neurological disorders. We summarize the pathological mechanisms underlying central nervous system diseases and discuss how cell membrane-coated nanocarriers derived from red blood cells, platelets, immune cells, stem cells, and cancer cells can enhance BBB penetration, immune evasion, and targeted delivery. A comprehensive literature search was conducted using PubMed, Scopus, Web of Science, and Google Scholar to evaluate therapeutic and diagnostic applications in Alzheimer's disease, Parkinson's disease, multiple sclerosis, autism spectrum disorder, ischemic stroke, and glioblastoma.

EXPERT OPINION: Biomimetic nanocarriers offer a promising strategy to overcome biological barriers and improve central nervous system drug delivery. However, clinical translation remains challenged by membrane source standardization, scalability, and safety concerns. Future research should focus on reproducible manufacturing, regulatory frameworks, and long-term toxicity evaluation to accelerate clinical adoption.},
}

@article {pmid41964958,
year = {2026},
author = {Fukui, M and Kaise, T and Masaki, T and Sakamoto, T and Kageyama, R},
title = {Activation of neurogenesis improves amyloid-β pathology and cognitive function through AMP kinase signaling in Alzheimer's disease model mice.},
journal = {Cell reports},
volume = {45},
number = {4},
pages = {117250},
doi = {10.1016/j.celrep.2026.117250},
pmid = {41964958},
issn = {2211-1247},
abstract = {Adult hippocampal neurogenesis declines with aging and in neurological disorders, leading to cognitive impairment. We previously showed that inducing Plagl2 and antagonizing Dyrk1a (iPaD) rejuvenates aged neural stem cells (NSCs), enhancing neurogenesis and cognition in aged mice. Here, we found that NSC-specific iPaD treatment activates neurogenesis, reduces amyloid-β deposition, and improves cognition in Alzheimer's disease model mice. Transcriptomic analysis revealed widespread changes in gene expression in the hippocampus after iPaD treatment. The upregulated genes include those associated with astrocyte and microglial activation involved in amyloid-β clearance, while several genes upregulated in Alzheimer's disease are downregulated. Among the latter genes, knockdown of Prkag2 in the hippocampus most effectively enhances neurogenesis and reduces amyloid-β accumulation. Notably, both iPaD treatment and Prkag2 knockdown activate AMP-activated protein kinase signaling, upregulating genes involved in autophagy and cellular homeostasis. These results suggest that Prkag2 may represent a promising therapeutic target for neurodegenerative diseases, including Alzheimer's disease.},
}

@article {pmid41965638,
year = {2026},
author = {Khan, AJ and Rahman, I and Beg, HA and Akter, S and Haque, R and Monsur, DT and Rani, H and Dom, TNM},
title = {Association of periodontitis and tooth loss with cognitive decline in the older adults - a systematic review.},
journal = {BMC oral health},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12903-026-08310-w},
pmid = {41965638},
issn = {1472-6831},
abstract = {BACKGROUND: The increasing global burden of dementia highlights the importance of identifying factors that may contribute to cognitive decline in later life. Growing evidence suggests that chronic oral conditions, particularly periodontitis (PD) and tooth loss, may be associated with Alzheimer's disease (AD) and related dementias. This study synthesizes current observational evidence on the association between PD, tooth loss, and cognitive impairment (CI) among older adults.

METHODS: A comprehensive literature search was conducted in PubMed, the Cochrane Library, Embase, Scopus, and Google Scholar for English-language studies published between 2010 and 2025. Cross-sectional and longitudinal cohort studies examining associations between PD, tooth loss, and CI were included. Study selection, data extraction, and quality assessment were performed in accordance with PRISMA 2020 guidelines.

RESULTS: Thirteen studies met the inclusion criteria, with sample sizes ranging from 40 participants to over 500,000 individuals in large population-based cohorts. Most studies focused on adults aged ≥ 50 years, particularly those aged 60 years and above. Periodontal status, tooth loss, and cognitive outcomes were assessed using heterogeneous diagnostic methods. Most studies reported significant associations between PD or tooth loss and CI, dementia, or AD. Periodontal treatment appeared protective in several studies, although some associations weakened after adjustment for confounders.

CONCLUSIONS: The findings support PD and tooth loss are consistently associated with adverse cognitive outcomes, although causal relationships cannot be established due to methodological heterogeneity and residual confounding. Integrating oral health care into geriatric and dementia-prevention strategies may help preserve cognitive function and improve quality of life among older adults.},
}

@article {pmid41965896,
year = {2026},
author = {Wang, J and Chen, L and Wang, Z and Chen, XY and Zhang, S and Ding, D and Zhou, Y and Rager-Aguiar, R and Lin, G and Zhang, H and Boda, VK and Ortyl, TC and Nelson, PT and Bezprozvanny, I and Zhou, FM and Du, J and Wu, Z and Li, W and Liao, FF},
title = {Pyrazole-derived TRPC3 antagonist ameliorates synaptic dysfunctions and memory deficits in Alzheimer's disease models.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41965896},
issn = {1476-5578},
abstract = {Transient receptor potential canonical (TRPC) channels are widely expressed in the brain; however, their precise roles in neurodegenerative diseases, such as Alzheimer's disease (AD), remain elusive. We found that TRPC3 expression is upregulated in excitatory neurons of brains with AD. We tested a selective inhibitor (JW-65) for TRPC3 over TRPC6 to investigate the potentially distinct role of TRPC3 in AD. JW-65 treatment significantly restored impaired synaptic plasticity and learning memory in acute and chronic experimental AD models. JW-65 treatment of late symptomatic 5XFAD transgenic mice reversed the impaired LTP, correlating with their significantly corrected synaptic gene expression based on hippocampal RNA-seq data analysis. JW-65 also provided synaptic protection in primary rat hippocampal neurons against soluble β-amyloid oligomers (AβOs), primarily via restoring the AβOs-impaired Ca[2+]/calmodulin-mediated signaling pathways. JW-65 treatment also significantly prevented Ca[2+] overload induced by AβOs. These findings suggest that aberrantly upregulated TRPC3, as a novel non-selective ion channel, significantly contributes to Ca[2+] dyshomeostasis in AD. Our work identifies TRPC3 as a potential therapeutic target for treating or preventing synaptic dysfunction of AD.},
}

@article {pmid41966037,
year = {2026},
author = {Qudoos, MA and Elliott, DP},
title = {Review of Donanemab and Lecanemab in Mild Dementia Stage of Alzheimer's Disease: Progress and Challenges.},
journal = {The Senior care pharmacist},
volume = {41},
number = {3},
pages = {98-108},
doi = {10.4140/TCP.n.2026.98},
pmid = {41966037},
issn = {2639-9636},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects ; *Antibodies, Monoclonal/therapeutic use/adverse effects ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline and functional impairment, primarily driven by the accumulation of amyloid-beta (Aβ) plaques and tau tangles. Historically, treatments have focused on symptomatic relief; however, recent therapeutic advances have focused on disease-modifying monoclonal antibodies (mAbs), notably lecanemab and donanemab, which target Aβ pathology in early-stage AD. This review explores the clinical efficacy, safety profile, and limitations of lecanemab and donanemab, emphasizing key findings from the CLARITY-AD and TRAILBLAZER-ALZ 2 trials. In these studies, lecanemab was shown to slow cognitive decline by 27% over 18 months, while donanemab achieved a 28.9% reduction over 76 weeks, with the greatest benefits observed in patients presenting with lower baseline tau pathology.Despite these promising outcomes, challenges remain, including possible reduced efficacy in women based on subgroup analyses of trial data, racial disparities in trial representation, adverse effects such as amyloid-related imaging abnormalities (ARIA), and substantial cost and accessibility barriers. This review underscores the need for more inclusive research, personalized treatment strategies, and continued exploration of AD's complex pathology beyond amyloid clearance.},
}

Humans
*Alzheimer Disease/drug therapy
*Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects
*Antibodies, Monoclonal/therapeutic use/adverse effects
Amyloid beta-Peptides/metabolism

@article {pmid41966346,
year = {2026},
author = {Matuszewska, M and Cieślik, M and Sulejczak, D and Wilkaniec, A and Czapski, GA},
title = {BET protein inhibitor JQ1 reduces inflammationand hippocampal amyloid-β level without altering Tau phosphorylation in LPS-challenged adult wild-type mice.},
journal = {Brain research},
volume = {},
number = {},
pages = {150318},
doi = {10.1016/j.brainres.2026.150318},
pmid = {41966346},
issn = {1872-6240},
abstract = {A growing body of evidence highlights the role of infection and inflammation in the progression of Alzheimer's disease (AD). In this study, we aimed to analyze the impact of JQ1, an inhibitor of bromodomain and extraterminal domain (BET) proteins, which are key readers of the epigenetic acetylation code, on AD-related gene expression changes and biochemical alterations in the hippocampus during a lipopolysaccharide (LPS)-induced systemic inflammatory response in mice. JQ1 and LPS were administered intraperitoneally to adult male wild-type C57BL/6J mice. Changes in selected general and brain-specific parameters were measured for up to 12 h. Our results demonstrated that inhibition of BET proteins reduced LPS-induced sickness behavior and time-dependent elevation of proinflammatory signaling. LPS did not significantly alter amyloid-β (Aβ) levels; however, a significant reduction in Aβ load was observed in JQ1-treated animals overall, suggesting that BET proteins play a crucial role in regulating Aβ levels in the brain. At the same time, JQ1 treatment did not affect LPS-induced increases in phospho-Tau levels. Our results suggest that inhibiting BET proteins, in addition to their anti-inflammatory action, may be an effective strategy for reducing Aβ levels in the brain. However, a mechanistic explanation of this phenomenon requires further investigation.},
}

@article {pmid41966670,
year = {2026},
author = {Kaur, N and Gupta, S and Bansal, G and Bansal, Y},
title = {BACE-1 inhibitors as potential drug candidates for treatment of Alzheimer's disease: a systematic review.},
journal = {Molecular diversity},
volume = {},
number = {},
pages = {},
pmid = {41966670},
issn = {1573-501X},
}

@article {pmid41956234,
year = {2026},
author = {Alves, SS and Manzine, PR and Dos Santos, FM and Migliaccio, MM and de Carvalho Alves, LV and da Silva Junior, RMP and Becerra-Hernández, LV and González-Acosta, CA and Buriticá-Ramírez, E and Cominetti, MR and Camins, A and Garcia-Cairasco, N},
title = {From comorbidity to continuum: Alzheimer's disease and epilepsy are connected-now what?.},
journal = {Neuroscience and biobehavioral reviews},
volume = {},
number = {},
pages = {106682},
doi = {10.1016/j.neubiorev.2026.106682},
pmid = {41956234},
issn = {1873-7528},
abstract = {Alzheimer's disease (AD) and epilepsy are increasingly recognized not merely as comorbid conditions but as disorders lying along a shared pathophysiological continuum, characterized by overlapping clinical features, network hyperexcitability, and convergent molecular mechanisms. Although bidirectional interactions between AD and epilepsy are now well established, critical questions remain regarding how this knowledge can be translated into improved risk prediction, prevention, and treatment. Classical mechanisms such as amyloid-β and tau pathology, neuroinflammation, and synaptic dysfunction, together with less explored processes including brain insulin resistance, converge on shared downstream effects that promote both neurodegeneration and epileptogenesis. However, marked mechanistic heterogeneity across individuals, limits standardized therapeutic approaches and complicates the prediction of seizure risk in AD and dementia risk in epilepsy. In this review, we synthesize evidence supporting the AD-epilepsy continuum, integrating molecular pathways, genetic and metabolic modifiers, fluid biomarkers, and neuroimaging signatures that may enable earlier identification of vulnerable trajectories. We critically examine pharmacological strategies with dual effects on neuroprotection and seizure control and discuss how targeting shared mechanisms may shift interventions from symptomatic management toward disease modification. Importantly, we highlight current gaps and emerging hypotheses that define the next steps for the field, including patient stratification, early biomarker-guided trial design, and precision-based therapeutic strategies. By moving beyond descriptive associations, this review outlines a framework for translating mechanistic insight into actionable approaches aimed at early detection, personalized intervention, and improved outcomes in individuals at risk across the AD-epilepsy spectrum.},
}

@article {pmid41956992,
year = {2026},
author = {Papapanagiotou, O and Cotton, K and Edwards, C and Michod, D and Crompton, L and Craig, T and Niklison-Chirou, MV},
title = {Lipid droplets in neurodegenerative diseases: pathological drivers and therapeutic vulnerabilities.},
journal = {Cell death discovery},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41420-026-03096-w},
pmid = {41956992},
issn = {2058-7716},
abstract = {Lipid droplets (LDs) are dynamic intracellular organelles traditionally associated with energy storage, which have become increasingly recognised for their versatile roles in cellular metabolism and signalling. In the brain, LDs have emerged as critical regulators in neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), and Hereditary Spastic Paraplegia (HSP). LDs contribute to neurodegeneration by influencing lipid metabolism, oxidative stress, and inflammatory responses. For instance, in AD, dysregulated lipid metabolism and impaired Apolipoprotein E 4 (ApoE4) function lead to LD accumulation associated with neuroinflammation and amyloid plaque formation. In PD, interactions between LDs and α-synuclein suggest a potential link between lipid dysregulation and neurotoxicity. Mutations in LD-associated proteins, such as spastin and DDH2 in HSP, highlight the importance of proper LD regulation for neuronal health. While LD accumulation can be protective by mitigating lipotoxicity, prolonged dysregulation can exacerbate NDD pathology. Targeting LD metabolism, through enhancing lipophagy or modulating LD-associated proteins, represents a promising therapeutic avenue. This review highlights the dual roles of LDs in the brain, acting both neuroprotectively and neurotoxically, and the therapeutic potential of targeting LD dynamics for NDD treatment.},
}

@article {pmid41957314,
year = {2026},
author = {Park, Y and Chae, H and Yoon, E and Kim, Y and Han, JW and Woo, SJ and Yoo, S and Kim, KW},
title = {Restoration of gamma center frequency via personalized entrainment marks cognitive preservation in early Alzheimer's disease.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41957314},
issn = {2509-2723},
support = {NRF-2017R1A5A1014708//National Research Foundation of Korea/ ; RS-2025-02223212//Korea Health Industry Development Institute/Republic of Korea ; },
abstract = {Gamma entrainment shows promise for Alzheimer's disease (AD) treatment in preclinical models, but human trials have yielded heterogeneous results. We hypothesized that the clinical efficacy of gamma entrainment depends on individual neurophysiological receptivity, specifically the capacity for neural circuit plasticity. In this open-label pilot study, we screened 37 individuals and enrolled 16 participants with early AD (CDR 0.5-1.0, amyloid-positive) who completed 12 weeks of home-based flickering light stimulation at individually optimized gamma frequencies (32-40 Hz). Pre- and post-intervention assessments included 64-channel EEG recordings and MMSE. Participants demonstrated dichotomous neurophysiological responses: 43.8% showed center frequency (CF) increase (increased CF [ICF+]) while 56.3% showed no change/decrease (non-increased CF [ICF-]). CF restoration was significantly associated with cognitive preservation (r = 0.52, p = 0.039). Notably, future responders exhibited distinct baseline signatures of "neural reserve," characterized by higher temporal gamma power (Cohen's d = 0.70-0.92) and stronger frontotemporal connectivity (Cohen's d = 1.11-1.47). Almost 30% of screened candidates failed to show baseline entrainment, highlighting a distinct "non-responsive" biological subtype. CF restoration following personalized gamma entrainment identifies a neurophysiological subtype capable of meaningful plasticity. Rather than a universal remedy, gamma entrainment appears to act on specific neural substrates preserved in a subset of patients. These findings suggest that baseline electrophysiological profiling could unlock gamma entrainment's therapeutic potential by stratifying likely responders for precision neuromodulation.},
}

@article {pmid41957960,
year = {2022},
author = {Li, CT and Fuh, JL and Yang, BH and Hong, CJ and Chang, CW and Tu, PC and Jeng, JS and Chen, MH and Tsai, SJ and Bai, YM and Su, TP and Lee, H and Huang, WS},
title = {Global cognitive dysfunction and β-amyloid neuropathology in late-life and treatment-resistant major depression.},
journal = {Psychological medicine},
volume = {52},
number = {16},
pages = {4116-4126},
doi = {10.1017/S0033291721001070},
pmid = {41957960},
issn = {1469-8978},
abstract = {BACKGROUND: Cognitive impairment is common in late-life depression, which may increase Alzheimer disease (AD) risk. Therefore, we aimed to investigate whether late-life major depressive disorder (MDD) has worse cognition and increases the characteristic AD neuropathology. Furthermore, we carried out a comparison between treatment-resistant depression (TRD) and non-TRD. We hypothesized that patients with late-life depression and TRD may have increased β-amyloid (Aβ) deposits in brain regions responsible for global cognition.

METHODS: We recruited 81 subjects, including 54 MDD patients (27 TRD and 27 non-TRD) and 27 matched healthy controls (HCs). Neurocognitive tasks were examined, including Mini-Mental State Examination and Montreal Cognitive Assessment to detect global cognitive functions. PET with Pittsburgh compound-B and fluorodeoxyglucose were used to capture brain Aβ pathology and glucose use, respectively, in some patients.

RESULTS: MDD patients performed worse in Montreal Cognitive Assessment (p = 0.003) and had more Aβ deposits than HCs across the brain (family-wise error-corrected p < 0.001), with the most significant finding in the left middle frontal gyrus. Significant negative correlations between global cognition and prefrontal Aβ deposits existed in MDD patients, whereas positive correlations were noted in HCs. TRD patients had significantly more deposits in the left-sided brain regions (corrected p < 0.001). The findings were not explained by APOE genotypes. No between-group fluorodeoxyglucose difference was detected.

CONCLUSIONS: Late-life depression, particularly TRD, had increased brain Aβ deposits and showed vulnerability to Aβ deposits. A detrimental role of Aβ deposits in global cognition in patients with late-onset or non-late-onset MDD supported the theory that late-life MDD could be a risk factor for AD.},
}

@article {pmid41959105,
year = {2026},
author = {Burberry, A and Benchek, P and Lowe, M and Shin, W and McCourt, B and Beamon, Q and Chakrabarti, S and Ramaiah, S and Woidke, E and Khrestian, M and Maecker, H and Bekris, LM and Rao, S and Ontaneda, D and Leverenz, JB and Bush, W and Pillai, JA},
title = {Early peripheral immune signaling precedes tau elevation and blood-brain barrier disruption in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.02.716122},
pmid = {41959105},
issn = {2692-8205},
abstract = {Neuroinflammation, along with amyloid beta (Aβ) deposition, phospho-tau (ptau) accumulation, blood-brain barrier (BBB) disruption, and cognitive decline are recognized components of Alzheimer's disease (AD). However, the timing and nature of peripheral immune changes across AD biological and clinical stages remain poorly understood. Here we performed mass cytometry profiling of whole blood and cerebrospinal fluid (CSF) immune cells from 351 human samples across two independent clinical cohorts spanning the AD continuum. We identify coordinated peripheral immune signaling signatures that emerge during preclinical stage of AD and precede significant elevation of plasma ptau217, CSF ptau181 and BBB disruption measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). AD-enriched immune features, including increased phospho-Akt signaling in naï ve T killer cells and phospho-PLCγ2 signaling in granulocytes, were not observed in patients with Frontotemporal lobar degeneration or treatment-naï ve multiple sclerosis. Furthermore, these immune signaling states could be induced in healthy donor immune cells following exposure to plasma or CSF from individuals with AD, indicating that circulating factors can drive these peripheral immune alterations. Together, our findings demonstrate that dynamic peripheral immune state changes arise early in AD and precede canonical biomarker and vascular changes, highlighting immune signaling pathways as potential targets for early therapeutic intervention.},
}

@article {pmid41959530,
year = {2026},
author = {Pandey, S and Talo, M and Siderovski, DP and Sumien, N and Bozdag, S},
title = {From General-Purpose to Disease-Specific Features: Aligning LLM Embeddings on a Disease-Specific Biomedical Knowledge Graph for Drug Repurposing.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.07.707871},
pmid = {41959530},
issn = {2692-8205},
abstract = {Identifying new therapeutic uses for existing drugs is a major challenge in biomedicine, especially for complex neurodegenerative conditions such as Alzheimer disease and related dementias (ADRD), where treatment options remain limited and relevant data are often sparse, heterogeneous, and difficult to integrate. Although general-purpose Large Language Model (LLM) embeddings encode rich semantic information, they often lack the task-specific biomedical context needed for inference tasks such as computational drug repurposing. We introduce Contextualizing LLM Embeddings via Attention-based gRaph learning (CLEAR), a multimodal representation-fusion framework that aligns LLM embeddings with the topological structure of a context-specific Knowledge Graph (KG). Across five benchmark datasets, CLEAR achieved state-of-the-art results, improving predictive performance (e.g., F1 score) by up to 30% over prior methods. We further applied CLEAR to identify FDA-approved drugs with potential for repurposing for ADRD, including Parkinson disease-related dementia and Lewy Body dementia. CLEAR learned a biologically coherent embedding space, prioritized leading ADRD drug candidates, and accurately summarized known therapeutic relationships for FDA-approved Alzheimer disease drugs. Overall, CLEAR shows that grounding biomedical LLM embeddings with context-specific KG signals can improve drug repurposing in data-sparse, real-world settings. GitHub: https://github.com/bozdaglab/CLEAR.},
}

@article {pmid41959743,
year = {2026},
author = {Guo, Y and Jiang, Q and Gu, Z and Cao, H and Zuo, C and Huang, Y and Song, Y and Chen, X and Wang, F},
title = {ACSL4 in Alzheimer's disease: Pathogenetic mechanisms and potential therapeutic targets.},
journal = {Genes & diseases},
volume = {13},
number = {4},
pages = {101858},
pmid = {41959743},
issn = {2352-3042},
abstract = {Iron metabolism plays a vital role in maintaining physiological homeostasis, and its dysregulation is implicated in a range of pathological consequences and illnesses, including Alzheimer's disease (AD). Prior studies have demonstrated that Tau protein and amyloid precursor protein are involved in iron homeostasis disorder. Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a key contributor to AD pathogenesis and a promising therapeutic target. Acyl-CoA synthetase long-chain family 4 (ACSL4) is a lipid metabolizing enzyme that enhances ferroptosis sensitivity by promoting the incorporation of oxidizable polyunsaturated fatty acids into membrane phospholipids. Beyond ferroptosis, ACSL4 also plays crucial roles in neuroinflammation and oxidative stress, which are implicated in AD progression. Therefore, targeting ACSL4 is fantastic and has a lot of promise for treating AD. Nevertheless, the precise mechanisms through which ACSL4 contributes to AD pathology have yet to be fully elucidated. This review reveals a potentially vital role of ACSL4 in AD, focusing on its involvement in ferroptosis, oxidative stress, and neuroinflammation. Additionally, we describe some natural and synthetic compounds targeting ACSL4 with therapeutic potential in AD. Building on the theoretical findings of earlier studies about focused interventions of the ACSL4 path, our evaluation provided a broad basis for the clinical transformation in the treatment of AD strategies.},
}

@article {pmid41961243,
year = {2026},
author = {Porsteinsson, AP and Chumki, SR and Wang, D and Such, P and Palma, AM and Zhang, Z and Shah, A and Kalu, U and Montano, CB},
title = {Short-Term and Long-Term Safety Analyses of Brexpiprazole for Agitation Associated with Dementia due to Alzheimer's Disease: Timing and Duration of Adverse Events.},
journal = {Drug safety},
volume = {},
number = {},
pages = {},
pmid = {41961243},
issn = {1179-1942},
abstract = {INTRODUCTION: Agitation symptoms are a common and burdensome aspect of Alzheimer's dementia. Historically, agitation has been managed using off-label treatments such as atypical antipsychotics, but this approach is associated with safety concerns in older, more vulnerable patients. Brexpiprazole is an atypical antipsychotic that has been recently approved in several countries for the treatment of agitation associated with dementia due to Alzheimer's disease. Previous analyses show that brexpiprazole was efficacious and generally well tolerated for up to 24 weeks. Building upon previous work, this post hoc analysis aimed to evaluate the timing and duration of treatment-emergent adverse events (TEAEs) during brexpiprazole treatment.

METHODS: In a 12-week analysis, data were pooled from three phase 3, randomized, double-blind, placebo-controlled trials of brexpiprazole in participants with agitation associated with dementia due to Alzheimer's disease. In a separate 24-week analysis, brexpiprazole data were combined from a 12-week randomized trial and a 12-week active-treatment extension trial. The median time from starting treatment to first reporting a TEAE and the median duration of all TEAEs were determined.

RESULTS: A total of 1043 participants received at least one dose of trial medication. Over 12 weeks, brexpiprazole 2 or 3 mg/day (the approved therapeutic dosages in the United States, N = 366) compared to placebo (N = 388) had similar time to first TEAE (32 days and 28 days, respectively), similar duration of all TEAEs (6 days and 4 days), and longer time to discontinuation due to adverse events (47 days and 30 days). Over 24 weeks (N = 163), the time to first TEAE on brexpiprazole 2 or 3 mg/day was 52 days, and the duration of all TEAEs was 3 days. Among participants who did not report a TEAE in the 12-week parent trial, TEAEs were rare throughout the 12-week extension trial.

CONCLUSIONS: These exploratory analyses reinforce that brexpiprazole is generally well tolerated over 12 weeks, and also over 24 weeks among patients who tolerated the first 12 weeks of treatment. The results provide a practical clinical insight into the safety of brexpiprazole over time in patients with agitation associated with dementia due to Alzheimer's disease.

TRIAL REGISTRATION: Post hoc analysis of NCT01862640, NCT01922258, NCT03548584, NCT03594123 (ClinicalTrials.gov).},
}

@article {pmid41961641,
year = {2026},
author = {Yang, L and Zhao, W and Zhao, J and Chen, S and Qin, X and Yang, Z and Kong, D and Zhang, W},
title = {Effects of ononin on cognitive and learning-memory functions in mild cognitive impairment.},
journal = {Neuroreport},
volume = {},
number = {},
pages = {},
doi = {10.1097/WNR.0000000000002264},
pmid = {41961641},
issn = {1473-558X},
abstract = {OBJECTIVE: This study aimed to investigate the potential of ononin in alleviating mild cognitive impairment (MCI) and to determine whether its effects depend on the functional recovery of neurons in the nucleus tractus solitarius (NTS).

METHODS: Four-month-old APP/PS1 mice were treated with 30-mg/kg ononin via oral gavage for 8 consecutive days. Cognitive behavior was assessed using the novel object recognition test, Y-maze test, and open field test. Cortical perfusion was measured by laser speckle contrast imaging. The activation of NTS neurons was detected using c-Fos immunofluorescence staining, while dendritic complexity and neuronal firing frequency were evaluated via Golgi staining and patch-clamp electrophysiology, respectively.

RESULTS: Ononin treatment significantly improved the novel object recognition index and spontaneous alternation rate in the Y-maze test in APP/PS1 mice. It also enhanced cerebral blood flow perfusion and increased the number of c-Fos-positive cells in the NTS, hippocampal CA1 region, and cortex. Furthermore, ononin increased dendritic intersections and restored dendritic spine density in NTS neurons to normal levels, along with significantly elevating their firing frequency.

CONCLUSION: Ononin may ameliorate MCI-like cognitive deficits in APP/PS1 mice by activating NTS neurons, restoring synaptic plasticity, and improving cerebral perfusion. These findings suggest that the NTS could serve as a potential target for early intervention in Alzheimer's disease.},
}

@article {pmid41962111,
year = {2026},
author = {Sobiech, L and Wójcik, L and Jankowska, N and Turżańska, K},
title = {Periodontitis as a systemic inflammatory disorder - implications for cardiovascular and neurodegenerative diseases.},
journal = {Wiadomosci lekarskie (Warsaw, Poland : 1960)},
volume = {79},
number = {3},
pages = {646-650},
doi = {10.36740/WLek/218274},
pmid = {41962111},
issn = {0043-5147},
mesh = {Humans ; *Cardiovascular Diseases/etiology ; *Neurodegenerative Diseases/etiology ; *Periodontitis/complications/microbiology ; *Inflammation/complications ; },
abstract = {OBJECTIVE: Aim: Periodontitis is a chronic inflammatory condition associated with oral microbiome dysbiosis and the dominance of Gram-negative bacteria such as Porphyromonas gingivalis. It is characterized by progressive destruction of the supporting tissues of the tooth, leading to loss of connective tissue attachment, resorption of the alveolar bone, and, consequently to tooth loosening and loss. If left untreated, it leads to recurrent bacteremia and persistent systemic inflammation. The aim of this study is to discuss the mechanisms linking periodontitis to cardiovascular and neurodegenerative diseases.

PATIENTS AND METHODS: Materials and Methods: A comprehensive literature review was conducted examining clinical studies, systematic reviews, and meta-analyses assessing the impact of periodontal disease on the development of cardiovascular and neurodegenerative diseases.

CONCLUSION: Conclusions: Chronic activation of the immune response, oxidative stress, and lipid metabolism disorders promote endothelial dysfunction and the progression of atherosclerosis, increasing the risk of cardiovascular events. At the same time, systemic inflammation can affect the permeability of the blood-brain barrier and exacerbate neuroinflammatory processes, promoting β-amyloid accumulation and the progression of Alzheimer's disease. Analysis of the literature indicates the significant, albeit complex, nature of these relationships, emphasizing the importance of prevention and treatment of periodontal disease as part of comprehensive patient care. The key in the approach to periodontal patients is an interdisciplinary perspective, integrating dentistry, cardiology, neurology, and geriatrics.},
}

Humans
*Cardiovascular Diseases/etiology
*Neurodegenerative Diseases/etiology
*Periodontitis/complications/microbiology
*Inflammation/complications

@article {pmid41962274,
year = {2026},
author = {Dong, Y and Wang, Y and Chen, K and Sun, G and Cao, X and Li, X and Lu, W and Dai, X and Huang, B and Chen, Y},
title = {Engineering versatile nanoplatforms for calcium homeostasis modulation and broad-spectrum disease therapies.},
journal = {Biomaterials},
volume = {333},
number = {},
pages = {124207},
doi = {10.1016/j.biomaterials.2026.124207},
pmid = {41962274},
issn = {1878-5905},
abstract = {Calcium ions (Ca[2+]) serve as a pivotal intracellular second messenger, participating in core physiological processes including cell proliferation, neurotransmission, and apoptosis. The maintenance of calcium homeostasis depends on the precise interplay of plasma membrane channels and intracellular organelle stores. Dysregulation of calcium signaling is implicated in the pathogenesis of multiple diseases, including Alzheimer's disease, cancer, and cardiovascular disorders. Conventional pharmacological interventions are limited by off-target effects, insufficient bioavailability, and a lack of temporal and spatial control. Ca[2+]-regulated nanoplatform achieves spatiotemporally controlled drug release and responsive calcium level modulation through advanced surface engineering and stimulus-responsive design, substantially improving therapeutic precision and efficacy. Furthermore, nanoprobes permit real-time monitoring of calcium dynamics with high sensitivity and resolution. This comprehensive review systematically summarizes and highlights significant advances in engineering versatile nanoplatforms for calcium homeostasis modulation, focusing on constructed nanocarriers for drug delivery, functional nano-regulators for calcium flux intervention, and sensitive nanoprobes for real-time calcium imaging and quantification. Current challenges and future directions are also discussed to inspire the development of next-generation nanotheranostic platforms for precise diagnosis and treatment of calcium homeostasis-related diseases.},
}

@article {pmid41606687,
year = {2026},
author = {Wang, Y and Mohammadi, B and Hartmann, C and Hartmann, K and Thies, E and Matamoros-Angles, A and Fang, C and Harris, DA and Tatzelt, J and Altmeppen, HC and Sepulveda-Falla, D and Strittmatter, SM and Glatzel, M and Krasemann, S},
title = {Presymptomatic pharmacological inhibition of mGluR5 improves survival in a mouse model of prion diseases.},
journal = {Acta neuropathologica communications},
volume = {14},
number = {1},
pages = {},
pmid = {41606687},
issn = {2051-5960},
support = {P30 AG066508/AG/NIA NIH HHS/United States ; R01 AG034924/AG/NIA NIH HHS/United States ; },
abstract = {UNLABELLED: Toxic signaling of oligomeric protein species via binding to the cellular prion protein (PrP[C]) is implicated in various neurodegenerative diseases, including Alzheimer’s (AD) and Parkinson’s disease (PD). Metabotropic glutamate receptor 5 (mGluR5) has been identified as a PrP[C] signaling partner, and pharmacological inhibition of mGluR5 was shown to improve cognitive performance and rescue long-term-potentiation (LTP) impairment in both in vitro and in vivo models of AD and PD. Prion diseases are another group of fatal neurodegenerative disorders that are characterized by templated misfolding of endogenous PrP[C] itself into the disease-driving counterpart PrP[Sc]. Besides its role in the self-propagating misfolding cascade and aggregation, PrP[Sc] also acts as a toxic PrP[C] ligand in aberrant signaling through mGluR5. Therefore, targeting metabotropic glutamate receptors has been proposed as a therapeutic strategy for the intervention of prion disease. In this study, we investigated the impact of long-term oral administration of two different selective mGluR5 inhibitors, the negative allosteric inhibitor CTEP and a Silent Allosteric mGluR5 Modulator (SAM), in a mouse model of prion disease. Our findings demonstrate that treatment initiated during the preclinical phase significantly prolonged the survival of mice, whereas treatment starting after the onset of symptoms was no longer effective. Early treatment also delayed the formation of spongiosis, a pathological hallmark of prion diseases, but did not alter PrP[Res] levels. Preclinical dysregulation of mGluR5 could be shown in the mouse and a non-human primate model for prion diseases. Interestingly, in primary neurons, subacute treatment with CTEP blocked Aβ-induced, but not PrP[Sc]-associated synaptotoxicity. Thus, modes of action might differ markedly from those observed in models of Alzheimer’s disease. Together, although our data show that targeting mGluR5 may be an efficient therapy, however, since treatment needs to be started early during prion disease progression, the narrow therapeutic window limits its therapeutic application in human prion diseases.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-026-02235-9.},
}

@article {pmid41772032,
year = {2026},
author = {Zolfaghari, S and Gholizadeh, E and Garehdaghi, F},
title = {Integrating attractor dynamics and connectivity features for EEG-based dementia classification.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {41772032},
issn = {2045-2322},
abstract = {The precise differentiation between Alzheimer’s disease (AD) and frontotemporal dementia (FTD) presents a clinical challenge, as both conditions share overlapping symptoms yet diverge in their pathophysiological mechanisms and treatment strategies. Electroencephalography (EEG), characterized by its higher temporal resolution and widespread applicability, provides the opportunity to uncover subtle discrepancies in brain dynamics that may be difficult to detect with conventional neuroimaging techniques. This paper presents a system that combines nonlinear attractor-based features derived from phase-space representations with phase-locking value connectivity features to encapsulate both local and global brain dynamics. In this regard, resting-state EEG recordings from 36 AD patients, 23 FTD patients, and 29 healthy controls (HC) were preprocessed and analyzed to extract dynamic and network features. Multiple classifiers were then used to assess these features under stratified 10-fold cross-validation. The results showed that the support vector machine achieved the highest performance for AD vs. FTD (81.7%), logistic regression performed well for FTD vs. HC (81.0%), and gradient boosting reached 82.9% for AD vs. HC. These findings illustrate the capability of EEG as a low-cost diagnostic technique, suggest that attractor dynamics and connectivity can offer complementary perspectives on the brain alterations linked to dementia, and enhance classification performance.},
}

@article {pmid41772634,
year = {2026},
author = {Das, RK and Sahoo, N and Roy, D and Nguyen, L and Rodrigo, H and Duttaroy, AK and Fields, JA and Roy, U},
title = {Interferon-induced protein IFIT3 as a molecular nexus of neuroinflammation in Alzheimer's disease and HIV-associated neurocognitive disorders.},
journal = {Journal of neuroinflammation},
volume = {23},
number = {1},
pages = {},
pmid = {41772634},
issn = {1742-2094},
support = {SC2GM139715//UTRGV internal funding/ ; R15NS108815 and R01AI147731//National Institute of Health, USA/ ; P30AG059305//NASA-MUREP, NASA-MOSAIC, UTRGV-Resource Centers for Minority Aging Research (RCMAR)/ ; U54MD019970//NIMHD grant/ ; },
abstract = {UNLABELLED: Alzheimer’s disease (AD) and HIV-associated neurocognitive disorder (HAND) are significant global health concerns characterized by cognitive impairment and shared pathological features, including chronic neuroinflammation, amyloid deposition, and immune dysregulation. However, the precise molecular connections between these disorders remain unclear. Here, we identify IFIT3 as a critical shared mediator of neuroinflammatory responses in both AD and HAND. Using complementary approaches, including neuronal and microglial cell cultures, the APP/PS1 mouse model, and human postmortem brain tissues, we demonstrate consistent IFIT3 upregulation in response to amyloid-beta (Aβ) and HIV-1 exposure, with notably enhanced expression under combined conditions. Treatment with combination antiretroviral therapy (cART) partially mitigated IFIT3 induction. Additionally, siRNA-mediated silencing of IFIT3 significantly reduced key inflammatory mediators, including mitochondrial antiviral signaling protein (MAVS), nuclear factor-κB, and proinflammatory cytokines. Clinically, elevated IFIT3 expression was associated with early HAND and progressively increased across advancing AD Braak stages. Together, these findings identify IFIT3 as a potential molecular bridge between HAND and AD, highlighting its promise as both a biomarker and a therapeutic target for inflammation-driven neurodegeneration.

GRAPHICAL ABSTRACT: [Image: see text]

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-026-03713-6.},
}

@article {pmid41776457,
year = {2026},
author = {Tang, Y and Yang, R and Zhang, M and Zhou, C and Chen, M and Pan, H and Qin, Y and Gui, Y and Fan, G},
title = {Classifying drug-related problems of neurodegenerative diseases in the physician-pharmacist joint clinic of neurology: an application of the PCNE method.},
journal = {BMC geriatrics},
volume = {26},
number = {1},
pages = {},
pmid = {41776457},
issn = {1471-2318},
support = {22QA1411400//Shanghai Science and Technology Development Funds/ ; 81973289//National Natural Science Foundation of China/ ; },
abstract = {BACKGROUND: The prevalence of neurodegenerative diseases (NDDs) is escalating, and complex medication regimens lead to a high incidence of drug-related problems (DRPs). This study analyzes DRPs in this population to identify their incidence and causes. The findings aim to provide a theoretical basis for clinical intervention strategies and outpatient pharmacy monitoring, ultimately ensuring rational drug use and enhancing patient safety.

METHOD: This study was conducted among patients with neurodegenerative diseases at a major hospital in Shanghai, China, between July 2023 and June 2024. The Pharmaceutical Care Network Europe (PCNE) classification system version 9.1 was used to identify DRPs. Data was entered and analyzed using SPSS software. Full model and stepwise logistic regression analyses were used to identify predictors of DRP occurrence in the total sample and Alzheimer’s disease (AD)/Parkinson’s disease (PD) subgroups. Outpatient medications were summarized. A p-value of less than 0.05 was considered statistically significant.

RESULT: A total of 254 patients (90 AD, 171 PD) were involved, resulting in 398 DRPs. The most commonly encountered type of DRP was treatment effectiveness (48.99%), and drug selection (46.73%) was the most common cause. The majority of clinical pharmacist interventions were provided at the drug level (98.99%), primarily involving dose adjustment and usage method adjustment. The acceptance level of interventions by prescribers was high (90.70%), with the acceptance rate in AD patients (92.96%) being higher than that in PD patients (90.07%). Through pharmacist intervention, over 70% of DRPs were completely resolved. Anti-Parkinson’s disease drugs, antianxiety or antidepressant drugs, and sedatives and hypnotics were the three main drug classes contributing to DRPs. Lifestyle habits (smoking, drinking), the number of comorbidities, and the dose of medication were factors associated with the development of DRPs.

CONCLUSION: This study finding revealed that DRPs were prevalent in patients with PD and AD. Medication care was a protective factor, whereas polypharmacy and the presence of multiple comorbidities were significantly associated with an elevated risk of DRPs. Based on the PCNE classification and the “PCIAO” process, clinical pharmacists’ involvement in precision management offers a robust evidence base and provides clear guidance for optimizing therapeutic regimens.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12877-026-07234-y.},
}

@article {pmid41776637,
year = {2026},
author = {Wang, L and Wang, F and Wang, X and Chen, X and Li, C and Shan, K and Zhou, H and Wu, G and Xu, Z and Kong, X and Wei, P},
title = {The lung-brain axis: elucidating the mechanisms of pulmonary-driven neurological disorders.},
journal = {Journal of neuroinflammation},
volume = {23},
number = {1},
pages = {},
pmid = {41776637},
issn = {1742-2094},
support = {22201164//National Natural Science Foundation of China/ ; 82571352//National Natural Science Foundation of China/ ; QDZDZK-2025064//the Qingdao Key Health Discipline Development Fund/ ; ZR2024QH041//the Natural Science Foundation of Shandong Province/ ; QDKY2023ZD02//the Scientific Research Foundation of Qilu Hospital of Shandong University/ ; 2024M761822//China Postdoctoral Science Foundation/ ; },
abstract = {The brain and lungs represent two of the most vital organs in the human body. The conceptualization of the lung-brain axis has advanced our understanding of the bidirectional communication between the respiratory and central nervous systems. Accumulating evidence indicates that pulmonary diseases, including chronic obstructive pulmonary disease, asthma, acute respiratory distress syndrome and infections such as bacterial pneumonia, influenza and Coronavirus Disease 2019, along with airborne environmental exposures, constitute significant risk factors for various neurological disorders. The lung-brain axis is primarily mediated by microbial, immune, neural, metabolic and hormonal pathways. These mechanisms contribute to the disruption of blood-brain barrier integrity, the activation of neuroglial cells and the dysfunction of the cerebrovascular system, ultimately causing neuronal injury and diverse neurological conditions. Environmental factors, notably airborne particulate matter and chemical pollutants, further amplify the crosstalk among these mechanisms, extending the neurological risk. Here, we summarize the current knowledge regarding the association between pulmonary dysfunction and the development and progression of neurodegenerative diseases (such as Alzheimer’s disease and Parkinson’s disease), stroke, anxiety/depression, epilepsy, and migraine. Additionally, potential therapeutic strategies targeting the lung–brain axis are discussed to foster further research in this emerging field. Elucidating the complex interactions within the lung–brain axis will not only deepen our understanding of the shared pathophysiological mechanisms but also open novel avenues for the early diagnosis, prevention, and treatment of related neurological diseases.},
}

@article {pmid41776683,
year = {2026},
author = {Shin, H and Lee, S and Seo, W and Yoon, SH and Cho, I and Ye, S and Park, I and Yoon, S and Park, M and Kim, S and Lee, S and Kim, HY and Kim, I and Kim, Y},
title = {YIAD-0501 directly dissociates aggregates of full-length and N-terminal pyroglutamate-modified forms of Aβ.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {41776683},
issn = {1758-9193},
support = {RS-2018-NR031048//Basic Science Research Program, National Research Foundation of Korea (NRF), Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea/ ; RS-2025-00523607//Mid-Career Researcher Program, Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea/ ; RS-2021-NR059653//Mid-Career Researcher Program, Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea/ ; RS-2024-00349158//Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea/ ; RS-2024-00418203//Korea Institute for Advancement of Technology/ ; },
abstract = {BACKGROUND: Recent approvals of amyloid-β (Aβ) antibody drugs have established amyloid clearance as a viable therapeutic approach in Alzheimer’s disease (AD). However, despite substantial amyloid reduction, their cognitive benefits remain modest, potentially reflecting incomplete targeting of the structurally diverse pathogenic Aβ assemblies that drive AD progression. Given this molecular heterogeneity, a therapeutic strategy capable of targeting multiple toxic Aβ forms is required to achieve broader efficacy. To address this need, we investigated YIAD-0501, a small-molecule candidate designed to simultaneously engage multiple pathogenic Aβ species, including oligomeric and fibrillar forms of Aβ (1–42) and pyroglutamate Aβ(pE3–42).

METHODS: A series of 6H-furo[3,2-f]pyrrolo[1,2-d][1,4]diazepine derivatives was synthesized and screened by Thioflavin T fluorescence and A11 dot blot assays to identify compounds active against diverse pathogenic Aβ assemblies. The lead compound, YIAD-0501, was further characterized by transmission electron microscopy, circular dichroism, microscale thermophoresis, molecular docking, and amyloid plate mapping to define its Aβ interaction and structural effects. For in vivo evaluation, YIAD-0501 (10 mg/kg, daily for 4 weeks) was administered to 6-month-old male 5XFAD mice, followed by Y-maze testing for spatial working memory and contextual fear conditioning for hippocampal-dependent memory. Biochemical analyses, including immunoblotting, immunohistochemistry, and ELISA, were subsequently conducted to quantify Aβ plaque burden, soluble Aβ levels, and gliosis.

RESULTS: YIAD-0501 effectively reduced both oligomeric and fibrillar assemblies of Aβ (1–42) and Aβ(pE3–42) in vitro. Molecular docking and amyloid mapping analyses indicated interactions between YIAD-0501 and both the C-terminal hydrophobic region and the KLVFFA aggregation core of Aβ, consistent with the observed reduction in β-sheet content and direct binding. In 5XFAD mice, YIAD-0501 treatment decreased amyloid plaque burden, soluble Aβ levels, and neuroinflammation in the hippocampus, accompanied by improvements in spatial working and hippocampal-dependent memory.

CONCLUSIONS: Collectively, our findings identify YIAD-0501 as a small-molecule candidate that reduces multiple pathogenic Aβ assemblies and ameliorates hippocampal pathology and memory deficits in the 5XFAD mouse model. These findings highlight a chemically driven, multi-target mode of Aβ clearance, representing a strategy for broader intervention across the heterogeneous pathogenic landscape of AD.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-01999-5.},
}

@article {pmid41862973,
year = {2026},
author = {Marei, HE},
title = {Enhancer-based gene therapy: a new path for precision medicine.},
journal = {Hereditas},
volume = {163},
number = {},
pages = {},
pmid = {41862973},
issn = {1601-5223},
abstract = {Enhancers are critical cis-regulatory elements that regulate gene expression in a context-dependent manner by integrating transcription factor binding, chromatin state, and the three-dimensional organization of the genome. Recent advances in functional genomics and synthetic biology have increased interest in harnessing enhancer activity to regulate the expression of therapeutic genes. Unlike traditional approaches that rely on promoter-driven gene regulation, enhancer-based approaches can bias transgene expression toward specific cellular states or disease contexts; however, this control remains probabilistic and highly dependent on the chromatin environment. This review summarizes current knowledge of enhancer biology, discusses new strategies for utilizing enhancer function directly, and examines the potential benefits and drawbacks of using enhancer-based strategies for gene therapy applications. Often delivered using adeno-associated virus (AAV) vectors with tailored capsids, enhancers in gene therapy can be included into expression cassettes. Astrocyte- or microglia-specific enhancers in the brain enable enriched or preferential distribution of neuroprotective or immunomodulatory genes, hence lowering unintentional expression in non-target cell types. It is important to control gene expression for specific cell types for the treatment of neurodegenerative conditions such as Alzheimer’s or Parkinson’s disease, were unintentional gene expression results in negative consequences. However, the uses of enhancer-guided gene therapy go beyond the central nervous system. In cancer, therapeutic constructs are designed to inhibit oncogenic expression or induce tumor suppression pathways, using enhancers in either malignant or immune cells as a target. Similarly, through the use of tissue-specific enhancers in cardiovascular and regenerative medicine, lineage-enriched genes can be used to promote repair of damaged tissues and enhance functional recovery. Enhancer-based systems that modulate the levels of gene expression (enhancer systems that adjust gene expression to levels that are physiologically appropriate for a given cell type) may also be useful in diseases caused by imbalances of gene dosage (e.g., haploinsufficiency and copy number variations). However, despite the potential promise of enhancer-driven gene therapy, many technical and translational hurdles remain. Mapping and validating the function of cell-type-specific enhancers is hampered by the dynamic, context-dependent regulation of chromatin. The identification of enhancers across a variety of developmental stages and clinical states is being accelerated through the combination of recent advances in single-cell epigenomic techniques (e.g., ATAC-seq, ChIP-seq, and multi-omic integration). Recent advances in non-viral delivery methods and AAV capsid engineering are improving the safety, efficacy, and scalability of enhancer-driven gene therapies. However, there must be careful regulatory oversight to avoid unintentional activation of enhancers and ensure continuing efficacy of enhancer-guided therapies. This paper provides an overview of the conceptual basis of enhancer-driven gene therapies, the currently available applications, and barriers to their clinical application. We show how the combination of delivery technology, synthetic biology, and genomics is enabling new possibilities for tailored gene therapy particular to cell- and disease-specific. Enhancer-driven gene therapy could become an important component of next-generation precision medicine by addressing current challenges and using creative technology.},
}

@article {pmid41865008,
year = {2026},
author = {Borgström Bolmsjö, B and Barbosa Djärf, J and van Westen, D and Schindler, SE and Fawad, A and Collij, L and Smith, R and Mattsson-Carlgren, N and Stomrud, E and Tideman, P and Hansson, O and Palmqvist, S},
title = {Eligibility for amyloid targeting therapies among primary care patients with cognitive symptoms.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {},
pages = {},
pmid = {41865008},
issn = {1758-9193},
abstract = {BACKGROUND: Alzheimer’s disease (AD) is the most common cause of dementia and a growing healthcare challenge. Amyloid-targeting therapies (ATT) may slow progression, but implementation is limited by logistical and economic barriers. As primary care is the first contact for most patients with cognitive concerns, quantifying treatment eligibility in this setting is essential. The purpose of this study was to estimate the proportion of primary care patients presenting with cognitive symptoms who are eligible for ATT.

METHODS: This cohort study included patients presenting with cognitive symptoms in primary care across the region Skåne, in southern Sweden, recruited between January 2020 and April 2025. Stepwise exclusion criteria based on clinical diagnosis, comorbidities, and treatment contraindications were applied, in alignment with appropriate use recommendations for lecanemab and donanemab, respectively. Eligibility was further refined using CSF biomarkers (Aβ42/40 ratio), cognitive performance, and MRI findings.

RESULTS: In a full diagnostic work-up of 607 patients with sequential exclusions, 86 patients (14.2%) and 78 patients (12.8%) ultimately met the eligibility criteria for lecanemab and donanemab, respectively. Due to comorbidities, medication use, and age/BMI, around 1/3 of the original population was excluded. Most ineligible patients met more than one exclusion criterion. The eligible population was 63% female, mean age 77 years. Around 65% of the individuals had mild cognitive impairment (MCI), and 35% mild dementia.

CONCLUSIONS: About 13-14% of primary care patients evaluated for cognitive complaints were eligible for ATT. Compared with clinical trials, the eligible population was older and consisted of more women.

TRIAL REGISTRATION: BioFINDERPrimary Care study (NCT06120361, Registration date 2 November 2023 https//biofinder.se).

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-02019-2.},
}

@article {pmid41904593,
year = {2026},
author = {Merkel, J and Perneczky, R and Jessen, F and Frölich, L and Jansen, O and Peters, S and Berg, D and Schulz, JB and Bartsch, T},
title = {Amyloid-related imaging abnormalities (ARIA) in Alzheimer's disease: from pathophysiology to individualized risk assessment.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {},
pages = {},
pmid = {41904593},
issn = {1758-9193},
abstract = {UNLABELLED: Monoclonal antibodies targeting amyloid-β are the first approved disease-modifying treatment for Alzheimer’s disease. While amyloid-targeting therapies mitigate the progression of cognitive decline in early-stage Alzheimer’s disease, they are associated with amyloid-related imaging abnormalities (ARIA), an imaging phenomenon presenting as cerebral edema/effusion and/or hemorrhage. Redistribution of parenchymal amyloid-β to perivascular drainage pathways and direct antibody-amyloid interactions within the cerebral vasculature are considered key players in ARIA pathophysiology by promoting inflammation and vascular disruption, thus mirroring hallmarks of inflammatory cerebral amyloid angiopathy. Although ARIA is commonly regarded as an undesired side effect of amyloid-targeting therapies, its association with amyloid-β clearance from the brain opens up the possibility of an alternative interpretation as a physiological reaction to target engagement of anti-amyloid antibodies. Understanding risk factors that promote the occurrence of ARIA and its transformation from asymptomatic imaging phenomenon to its serious and severe form are of great importance to clinical practice. ARIA risk and severity are influenced by apolipoprotein E4 status, microvascular damage, and cerebral amyloid angiopathy, but may be further modulated by antibody binding preferences and comorbidities such as arterial hypertension and ischemic strokes. Identifying individual risk profiles based on deeper insights into pathophysiological pathways may improve patient safety and lead to personalized treatment concepts in Alzheimer’s disease. In this review, we provide a comprehensive summary of ARIA pathophysiology, highlight important risk factors and discuss their relevance in clinical risk management.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-02022-7.},
}

@article {pmid41946775,
year = {2026},
author = {Phemphunananchai, K and Waiwut, P and Phetcharaburanin, J and Poonsawas, P and Boonyarat, C},
title = {Repurposing FDA-approved drugs as multi-target neuroprotective agents for Alzheimer's disease via computational screening and experimental validation.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {41946775},
issn = {2045-2322},
support = {67-2(7)/2567//Faculty of Pharmaceutical Sciences, Khon Kaen University, Thailand/ ; RA2567-M109//The Research Assistant Program, Khon Kaen University, Thailand/ ; },
abstract = {UNLABELLED: β-site APP-cleaving enzyme 1 (BACE1, a β-secretase) is a key aspartyl protease that initiates the proteolytic processing of the amyloid precursor protein (APP) to form the amyloid-β (Aβ) peptide. Given that Aβ aggregation and plaque formation are a central pathological feature of Alzheimer’s disease (AD), BACE1 remains a critical therapeutic target. Furthermore, the complexity of AD pathology necessitates the identification of novel multi-target agents. This study employed a structure-based virtual screening, targeting the BACE1 approach to identify the potential BACE1 inhibitors from FDA-approved drug scaffolds derived from the ZINC database. Top-ranked candidates were subsequently validated through extensive 500 ns molecular dynamics (MD) simulations and in vitro assays of BACE1 inhibition activity. Furthermore, multi-AD-related target profiling of candidates was conducted using molecular docking and a series of in vitro assays. Among them, ZINC000019796155 emerged as a promising multi-target compound. Biochemical analysis revealed that ZINC000019796155 exhibited moderate inhibitory effects against BACE1. Subsequent assays confirmed its capacity to inhibit butyrylcholinesterase (BuChE) action and Aβ aggregation, function as a free radical scavenger, and provide neuroprotection against H2O2-induced oxidative stress in cellular models. Furthermore, western blot analysis elucidated the mechanism of neuroprotection, indicating that ZINC000019796155 inhibits the apoptotic pathway while simultaneously suppressing the formation of Aβ plaques and neurofibrillary tangles (NFTs). These findings highlight ZINC000019796155 as a validated scaffold with a known safety profile for AD. While further structural optimization and preclinical in vivo studies are necessary, this study underscores the potential of ZINC000019796155 as a multi-target neuroprotective agent for AD treatment.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-46708-2.},
}